A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC
Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due...
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Gespeichert in:
| Autor*in: |
Lu, Yue [verfasserIn] Fan, Zhenzhen [verfasserIn] Zhu, Su‐Jie [verfasserIn] Huang, Xiaoxing [verfasserIn] Zhuang, Zhongji [verfasserIn] Li, Yunzhan [verfasserIn] Deng, Zhou [verfasserIn] Gao, Lei [verfasserIn] Hong, Xuehui [verfasserIn] Zhang, Ting [verfasserIn] Li, Li [verfasserIn] Sun, Xihuan [verfasserIn] Huang, Wei [verfasserIn] Zhang, Jingfang [verfasserIn] Liu, Yan [verfasserIn] Zhang, Baoding [verfasserIn] Jiang, Jie [verfasserIn] Gui, Fu [verfasserIn] Wang, Zheng [verfasserIn] Li, Qiyuan [verfasserIn] Song, Siyang [verfasserIn] Huang, Xin [verfasserIn] Wu, Qiao [verfasserIn] Chen, Lanfen [verfasserIn] Zhou, Dawang [verfasserIn] Zhang, Jianming [verfasserIn] Yun, Cai‐Hong [verfasserIn] Chen, Liang [verfasserIn] Deng, Xianming [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2021 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 14(2021), 1 vom: 30. Nov. |
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| Übergeordnetes Werk: |
volume:14 ; year:2021 ; number:1 ; day:30 ; month:11 |
| Links: |
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| DOI / URN: |
10.15252/emmm.202114296 |
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| Katalog-ID: |
SPR058031847 |
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| 100 | 1 | |a Lu, Yue |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
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| 500 | |a © The Author(s) 2021 | ||
| 520 | |a Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. | ||
| 520 | |a Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. | ||
| 520 | |a Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. | ||
| 650 | 4 | |a acquired resistance mutations |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a ALK inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a crizotinib |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a EML4‐ALK |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a nonsmall cell lung cancer |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Fan, Zhenzhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Su‐Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Xiaoxing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Zhongji |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yunzhan |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Zhou |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Xuehui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xihuan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wei |e verfasserin |0 (orcid)0000-0002-6081-7878 |4 aut | |
| 700 | 1 | |a Zhang, Jingfang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Baoding |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Gui, Fu |e verfasserin |0 (orcid)0000-0001-8329-7118 |4 aut | |
| 700 | 1 | |a Wang, Zheng |e verfasserin |0 (orcid)0000-0002-3450-8254 |4 aut | |
| 700 | 1 | |a Li, Qiyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Siyang |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Qiao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lanfen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Dawang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jianming |e verfasserin |0 (orcid)0000-0001-6326-3906 |4 aut | |
| 700 | 1 | |a Yun, Cai‐Hong |e verfasserin |0 (orcid)0000-0002-5880-8307 |4 aut | |
| 700 | 1 | |a Chen, Liang |e verfasserin |0 (orcid)0000-0001-7300-6604 |4 aut | |
| 700 | 1 | |a Deng, Xianming |e verfasserin |0 (orcid)0000-0002-9354-5864 |4 aut | |
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10.15252/emmm.202114296 doi (DE-627)SPR058031847 (SPR)emmm.202114296-e DE-627 ger DE-627 rakwb eng Lu, Yue verfasserin aut A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 Fan, Zhenzhen verfasserin aut Zhu, Su‐Jie verfasserin aut Huang, Xiaoxing verfasserin aut Zhuang, Zhongji verfasserin aut Li, Yunzhan verfasserin aut Deng, Zhou verfasserin aut Gao, Lei verfasserin aut Hong, Xuehui verfasserin aut Zhang, Ting verfasserin aut Li, Li verfasserin aut Sun, Xihuan verfasserin aut Huang, Wei verfasserin (orcid)0000-0002-6081-7878 aut Zhang, Jingfang verfasserin aut Liu, Yan verfasserin aut Zhang, Baoding verfasserin aut Jiang, Jie verfasserin aut Gui, Fu verfasserin (orcid)0000-0001-8329-7118 aut Wang, Zheng verfasserin (orcid)0000-0002-3450-8254 aut Li, Qiyuan verfasserin aut Song, Siyang verfasserin aut Huang, Xin verfasserin aut Wu, Qiao verfasserin aut Chen, Lanfen verfasserin aut Zhou, Dawang verfasserin aut Zhang, Jianming verfasserin (orcid)0000-0001-6326-3906 aut Yun, Cai‐Hong verfasserin (orcid)0000-0002-5880-8307 aut Chen, Liang verfasserin (orcid)0000-0001-7300-6604 aut Deng, Xianming verfasserin (orcid)0000-0002-9354-5864 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 1 vom: 30. Nov. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:1 day:30 month:11 https://dx.doi.org/10.15252/emmm.202114296 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 14 2021 1 30 11 |
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10.15252/emmm.202114296 doi (DE-627)SPR058031847 (SPR)emmm.202114296-e DE-627 ger DE-627 rakwb eng Lu, Yue verfasserin aut A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 Fan, Zhenzhen verfasserin aut Zhu, Su‐Jie verfasserin aut Huang, Xiaoxing verfasserin aut Zhuang, Zhongji verfasserin aut Li, Yunzhan verfasserin aut Deng, Zhou verfasserin aut Gao, Lei verfasserin aut Hong, Xuehui verfasserin aut Zhang, Ting verfasserin aut Li, Li verfasserin aut Sun, Xihuan verfasserin aut Huang, Wei verfasserin (orcid)0000-0002-6081-7878 aut Zhang, Jingfang verfasserin aut Liu, Yan verfasserin aut Zhang, Baoding verfasserin aut Jiang, Jie verfasserin aut Gui, Fu verfasserin (orcid)0000-0001-8329-7118 aut Wang, Zheng verfasserin (orcid)0000-0002-3450-8254 aut Li, Qiyuan verfasserin aut Song, Siyang verfasserin aut Huang, Xin verfasserin aut Wu, Qiao verfasserin aut Chen, Lanfen verfasserin aut Zhou, Dawang verfasserin aut Zhang, Jianming verfasserin (orcid)0000-0001-6326-3906 aut Yun, Cai‐Hong verfasserin (orcid)0000-0002-5880-8307 aut Chen, Liang verfasserin (orcid)0000-0001-7300-6604 aut Deng, Xianming verfasserin (orcid)0000-0002-9354-5864 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 1 vom: 30. Nov. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:1 day:30 month:11 https://dx.doi.org/10.15252/emmm.202114296 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 14 2021 1 30 11 |
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10.15252/emmm.202114296 doi (DE-627)SPR058031847 (SPR)emmm.202114296-e DE-627 ger DE-627 rakwb eng Lu, Yue verfasserin aut A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 Fan, Zhenzhen verfasserin aut Zhu, Su‐Jie verfasserin aut Huang, Xiaoxing verfasserin aut Zhuang, Zhongji verfasserin aut Li, Yunzhan verfasserin aut Deng, Zhou verfasserin aut Gao, Lei verfasserin aut Hong, Xuehui verfasserin aut Zhang, Ting verfasserin aut Li, Li verfasserin aut Sun, Xihuan verfasserin aut Huang, Wei verfasserin (orcid)0000-0002-6081-7878 aut Zhang, Jingfang verfasserin aut Liu, Yan verfasserin aut Zhang, Baoding verfasserin aut Jiang, Jie verfasserin aut Gui, Fu verfasserin (orcid)0000-0001-8329-7118 aut Wang, Zheng verfasserin (orcid)0000-0002-3450-8254 aut Li, Qiyuan verfasserin aut Song, Siyang verfasserin aut Huang, Xin verfasserin aut Wu, Qiao verfasserin aut Chen, Lanfen verfasserin aut Zhou, Dawang verfasserin aut Zhang, Jianming verfasserin (orcid)0000-0001-6326-3906 aut Yun, Cai‐Hong verfasserin (orcid)0000-0002-5880-8307 aut Chen, Liang verfasserin (orcid)0000-0001-7300-6604 aut Deng, Xianming verfasserin (orcid)0000-0002-9354-5864 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 1 vom: 30. Nov. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:1 day:30 month:11 https://dx.doi.org/10.15252/emmm.202114296 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 14 2021 1 30 11 |
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10.15252/emmm.202114296 doi (DE-627)SPR058031847 (SPR)emmm.202114296-e DE-627 ger DE-627 rakwb eng Lu, Yue verfasserin aut A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 Fan, Zhenzhen verfasserin aut Zhu, Su‐Jie verfasserin aut Huang, Xiaoxing verfasserin aut Zhuang, Zhongji verfasserin aut Li, Yunzhan verfasserin aut Deng, Zhou verfasserin aut Gao, Lei verfasserin aut Hong, Xuehui verfasserin aut Zhang, Ting verfasserin aut Li, Li verfasserin aut Sun, Xihuan verfasserin aut Huang, Wei verfasserin (orcid)0000-0002-6081-7878 aut Zhang, Jingfang verfasserin aut Liu, Yan verfasserin aut Zhang, Baoding verfasserin aut Jiang, Jie verfasserin aut Gui, Fu verfasserin (orcid)0000-0001-8329-7118 aut Wang, Zheng verfasserin (orcid)0000-0002-3450-8254 aut Li, Qiyuan verfasserin aut Song, Siyang verfasserin aut Huang, Xin verfasserin aut Wu, Qiao verfasserin aut Chen, Lanfen verfasserin aut Zhou, Dawang verfasserin aut Zhang, Jianming verfasserin (orcid)0000-0001-6326-3906 aut Yun, Cai‐Hong verfasserin (orcid)0000-0002-5880-8307 aut Chen, Liang verfasserin (orcid)0000-0001-7300-6604 aut Deng, Xianming verfasserin (orcid)0000-0002-9354-5864 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 1 vom: 30. Nov. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:1 day:30 month:11 https://dx.doi.org/10.15252/emmm.202114296 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 14 2021 1 30 11 |
| allfieldsSound |
10.15252/emmm.202114296 doi (DE-627)SPR058031847 (SPR)emmm.202114296-e DE-627 ger DE-627 rakwb eng Lu, Yue verfasserin aut A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 Fan, Zhenzhen verfasserin aut Zhu, Su‐Jie verfasserin aut Huang, Xiaoxing verfasserin aut Zhuang, Zhongji verfasserin aut Li, Yunzhan verfasserin aut Deng, Zhou verfasserin aut Gao, Lei verfasserin aut Hong, Xuehui verfasserin aut Zhang, Ting verfasserin aut Li, Li verfasserin aut Sun, Xihuan verfasserin aut Huang, Wei verfasserin (orcid)0000-0002-6081-7878 aut Zhang, Jingfang verfasserin aut Liu, Yan verfasserin aut Zhang, Baoding verfasserin aut Jiang, Jie verfasserin aut Gui, Fu verfasserin (orcid)0000-0001-8329-7118 aut Wang, Zheng verfasserin (orcid)0000-0002-3450-8254 aut Li, Qiyuan verfasserin aut Song, Siyang verfasserin aut Huang, Xin verfasserin aut Wu, Qiao verfasserin aut Chen, Lanfen verfasserin aut Zhou, Dawang verfasserin aut Zhang, Jianming verfasserin (orcid)0000-0001-6326-3906 aut Yun, Cai‐Hong verfasserin (orcid)0000-0002-5880-8307 aut Chen, Liang verfasserin (orcid)0000-0001-7300-6604 aut Deng, Xianming verfasserin (orcid)0000-0002-9354-5864 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 14(2021), 1 vom: 30. Nov. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:14 year:2021 number:1 day:30 month:11 https://dx.doi.org/10.15252/emmm.202114296 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 14 2021 1 30 11 |
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Enthalten in EMBO Molecular Medicine 14(2021), 1 vom: 30. Nov. volume:14 year:2021 number:1 day:30 month:11 |
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Enthalten in EMBO Molecular Medicine 14(2021), 1 vom: 30. Nov. volume:14 year:2021 number:1 day:30 month:11 |
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Lu, Yue @@aut@@ Fan, Zhenzhen @@aut@@ Zhu, Su‐Jie @@aut@@ Huang, Xiaoxing @@aut@@ Zhuang, Zhongji @@aut@@ Li, Yunzhan @@aut@@ Deng, Zhou @@aut@@ Gao, Lei @@aut@@ Hong, Xuehui @@aut@@ Zhang, Ting @@aut@@ Li, Li @@aut@@ Sun, Xihuan @@aut@@ Huang, Wei @@aut@@ Zhang, Jingfang @@aut@@ Liu, Yan @@aut@@ Zhang, Baoding @@aut@@ Jiang, Jie @@aut@@ Gui, Fu @@aut@@ Wang, Zheng @@aut@@ Li, Qiyuan @@aut@@ Song, Siyang @@aut@@ Huang, Xin @@aut@@ Wu, Qiao @@aut@@ Chen, Lanfen @@aut@@ Zhou, Dawang @@aut@@ Zhang, Jianming @@aut@@ Yun, Cai‐Hong @@aut@@ Chen, Liang @@aut@@ Deng, Xianming @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058031847</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065236.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2021 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202114296</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058031847</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202114296-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Lu, Yue</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2021</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">acquired resistance mutations</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">ALK inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">crizotinib</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">EML4‐ALK</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">nonsmall cell lung cancer</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fan, 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| author |
Lu, Yue |
| spellingShingle |
Lu, Yue misc acquired resistance mutations misc ALK inhibitor misc crizotinib misc EML4‐ALK misc nonsmall cell lung cancer A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
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A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC acquired resistance mutations (dpeaa)DE-He213 ALK inhibitor (dpeaa)DE-He213 crizotinib (dpeaa)DE-He213 EML4‐ALK (dpeaa)DE-He213 nonsmall cell lung cancer (dpeaa)DE-He213 |
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Lu, Yue Fan, Zhenzhen Zhu, Su‐Jie Huang, Xiaoxing Zhuang, Zhongji Li, Yunzhan Deng, Zhou Gao, Lei Hong, Xuehui Zhang, Ting Li, Li Sun, Xihuan Huang, Wei Zhang, Jingfang Liu, Yan Zhang, Baoding Jiang, Jie Gui, Fu Wang, Zheng Li, Qiyuan Song, Siyang Huang, Xin Wu, Qiao Chen, Lanfen Zhou, Dawang Zhang, Jianming Yun, Cai‐Hong Chen, Liang Deng, Xianming |
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a new alk inhibitor overcomes resistance to first‐ and second‐generation inhibitors in nsclc |
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A new ALK inhibitor overcomes resistance to first‐ and second‐generation inhibitors in NSCLC |
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Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. © The Author(s) 2021 |
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Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. © The Author(s) 2021 |
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Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations. Synopsis Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models. Graphical Abstract Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC. © The Author(s) 2021 |
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