Loss of wild type
Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the inciden...
Ausführliche Beschreibung
Autor*in: |
Liu, Yan [verfasserIn] Gao, Galen F. [verfasserIn] Minna, John D. [verfasserIn] Williams, Noelle S. [verfasserIn] Westover, Kenneth D. [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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Übergeordnetes Werk: |
Enthalten in: Lung cancer - Amsterdam [u.a.] : Elsevier, 1985, 153, Seite 73-80 |
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Übergeordnetes Werk: |
volume:153 ; pages:73-80 |
DOI / URN: |
10.1016/j.lungcan.2020.12.032 |
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Katalog-ID: |
ELV005555124 |
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100 | 1 | |a Liu, Yan |e verfasserin |4 aut | |
245 | 1 | 0 | |a Loss of wild type |
264 | 1 | |c 2021 | |
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337 | |a Computermedien |b c |2 rdamedia | ||
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520 | |a Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. | ||
650 | 4 | |a Lung adenocarcinoma | |
650 | 4 | |a loss of heterozygosity | |
700 | 1 | |a Gao, Galen F. |e verfasserin |0 (orcid)0000-0003-3143-9270 |4 aut | |
700 | 1 | |a Minna, John D. |e verfasserin |4 aut | |
700 | 1 | |a Williams, Noelle S. |e verfasserin |0 (orcid)0000-0003-1894-5742 |4 aut | |
700 | 1 | |a Westover, Kenneth D. |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Lung cancer |d Amsterdam [u.a.] : Elsevier, 1985 |g 153, Seite 73-80 |h Online-Ressource |w (DE-627)320649733 |w (DE-600)2025812-4 |w (DE-576)264627539 |x 1872-8332 |7 nnns |
773 | 1 | 8 | |g volume:153 |g pages:73-80 |
912 | |a GBV_USEFLAG_U | ||
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912 | |a GBV_ILN_22 | ||
912 | |a GBV_ILN_23 | ||
912 | |a GBV_ILN_24 | ||
912 | |a GBV_ILN_31 | ||
912 | |a GBV_ILN_32 | ||
912 | |a GBV_ILN_40 | ||
912 | |a GBV_ILN_60 | ||
912 | |a GBV_ILN_62 | ||
912 | |a GBV_ILN_63 | ||
912 | |a GBV_ILN_65 | ||
912 | |a GBV_ILN_69 | ||
912 | |a GBV_ILN_70 | ||
912 | |a GBV_ILN_73 | ||
912 | |a GBV_ILN_74 | ||
912 | |a GBV_ILN_90 | ||
912 | |a GBV_ILN_95 | ||
912 | |a GBV_ILN_100 | ||
912 | |a GBV_ILN_101 | ||
912 | |a GBV_ILN_105 | ||
912 | |a GBV_ILN_110 | ||
912 | |a GBV_ILN_151 | ||
912 | |a GBV_ILN_224 | ||
912 | |a GBV_ILN_370 | ||
912 | |a GBV_ILN_602 | ||
912 | |a GBV_ILN_702 | ||
912 | |a GBV_ILN_2003 | ||
912 | |a GBV_ILN_2004 | ||
912 | |a GBV_ILN_2005 | ||
912 | |a GBV_ILN_2011 | ||
912 | |a GBV_ILN_2014 | ||
912 | |a GBV_ILN_2015 | ||
912 | |a GBV_ILN_2020 | ||
912 | |a GBV_ILN_2021 | ||
912 | |a GBV_ILN_2025 | ||
912 | |a GBV_ILN_2027 | ||
912 | |a GBV_ILN_2034 | ||
912 | |a GBV_ILN_2038 | ||
912 | |a GBV_ILN_2044 | ||
912 | |a GBV_ILN_2048 | ||
912 | |a GBV_ILN_2049 | ||
912 | |a GBV_ILN_2050 | ||
912 | |a GBV_ILN_2056 | ||
912 | |a GBV_ILN_2059 | ||
912 | |a GBV_ILN_2061 | ||
912 | |a GBV_ILN_2064 | ||
912 | |a GBV_ILN_2065 | ||
912 | |a GBV_ILN_2068 | ||
912 | |a GBV_ILN_2111 | ||
912 | |a GBV_ILN_2112 | ||
912 | |a GBV_ILN_2113 | ||
912 | |a GBV_ILN_2118 | ||
912 | |a GBV_ILN_2122 | ||
912 | |a GBV_ILN_2129 | ||
912 | |a GBV_ILN_2143 | ||
912 | |a GBV_ILN_2147 | ||
912 | |a GBV_ILN_2148 | ||
912 | |a GBV_ILN_2152 | ||
912 | |a GBV_ILN_2153 | ||
912 | |a GBV_ILN_2190 | ||
912 | |a GBV_ILN_2336 | ||
912 | |a GBV_ILN_2507 | ||
912 | |a GBV_ILN_2522 | ||
912 | |a GBV_ILN_4035 | ||
912 | |a GBV_ILN_4037 | ||
912 | |a GBV_ILN_4112 | ||
912 | |a GBV_ILN_4125 | ||
912 | |a GBV_ILN_4126 | ||
912 | |a GBV_ILN_4242 | ||
912 | |a GBV_ILN_4251 | ||
912 | |a GBV_ILN_4305 | ||
912 | |a GBV_ILN_4313 | ||
912 | |a GBV_ILN_4323 | ||
912 | |a GBV_ILN_4324 | ||
912 | |a GBV_ILN_4325 | ||
912 | |a GBV_ILN_4326 | ||
912 | |a GBV_ILN_4333 | ||
912 | |a GBV_ILN_4334 | ||
912 | |a GBV_ILN_4335 | ||
912 | |a GBV_ILN_4338 | ||
912 | |a GBV_ILN_4393 | ||
936 | b | k | |a 44.83 |j Rheumatologie |j Orthopädie |
951 | |a AR | ||
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44.83 |
publishDate |
2021 |
allfields |
10.1016/j.lungcan.2020.12.032 doi (DE-627)ELV005555124 (ELSEVIER)S0169-5002(20)30760-1 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Liu, Yan verfasserin aut Loss of wild type 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. Lung adenocarcinoma loss of heterozygosity Gao, Galen F. verfasserin (orcid)0000-0003-3143-9270 aut Minna, John D. verfasserin aut Williams, Noelle S. verfasserin (orcid)0000-0003-1894-5742 aut Westover, Kenneth D. verfasserin aut Enthalten in Lung cancer Amsterdam [u.a.] : Elsevier, 1985 153, Seite 73-80 Online-Ressource (DE-627)320649733 (DE-600)2025812-4 (DE-576)264627539 1872-8332 nnns volume:153 pages:73-80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 153 73-80 |
spelling |
10.1016/j.lungcan.2020.12.032 doi (DE-627)ELV005555124 (ELSEVIER)S0169-5002(20)30760-1 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Liu, Yan verfasserin aut Loss of wild type 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. Lung adenocarcinoma loss of heterozygosity Gao, Galen F. verfasserin (orcid)0000-0003-3143-9270 aut Minna, John D. verfasserin aut Williams, Noelle S. verfasserin (orcid)0000-0003-1894-5742 aut Westover, Kenneth D. verfasserin aut Enthalten in Lung cancer Amsterdam [u.a.] : Elsevier, 1985 153, Seite 73-80 Online-Ressource (DE-627)320649733 (DE-600)2025812-4 (DE-576)264627539 1872-8332 nnns volume:153 pages:73-80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 153 73-80 |
allfields_unstemmed |
10.1016/j.lungcan.2020.12.032 doi (DE-627)ELV005555124 (ELSEVIER)S0169-5002(20)30760-1 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Liu, Yan verfasserin aut Loss of wild type 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. Lung adenocarcinoma loss of heterozygosity Gao, Galen F. verfasserin (orcid)0000-0003-3143-9270 aut Minna, John D. verfasserin aut Williams, Noelle S. verfasserin (orcid)0000-0003-1894-5742 aut Westover, Kenneth D. verfasserin aut Enthalten in Lung cancer Amsterdam [u.a.] : Elsevier, 1985 153, Seite 73-80 Online-Ressource (DE-627)320649733 (DE-600)2025812-4 (DE-576)264627539 1872-8332 nnns volume:153 pages:73-80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 153 73-80 |
allfieldsGer |
10.1016/j.lungcan.2020.12.032 doi (DE-627)ELV005555124 (ELSEVIER)S0169-5002(20)30760-1 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Liu, Yan verfasserin aut Loss of wild type 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. Lung adenocarcinoma loss of heterozygosity Gao, Galen F. verfasserin (orcid)0000-0003-3143-9270 aut Minna, John D. verfasserin aut Williams, Noelle S. verfasserin (orcid)0000-0003-1894-5742 aut Westover, Kenneth D. verfasserin aut Enthalten in Lung cancer Amsterdam [u.a.] : Elsevier, 1985 153, Seite 73-80 Online-Ressource (DE-627)320649733 (DE-600)2025812-4 (DE-576)264627539 1872-8332 nnns volume:153 pages:73-80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 153 73-80 |
allfieldsSound |
10.1016/j.lungcan.2020.12.032 doi (DE-627)ELV005555124 (ELSEVIER)S0169-5002(20)30760-1 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Liu, Yan verfasserin aut Loss of wild type 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. Lung adenocarcinoma loss of heterozygosity Gao, Galen F. verfasserin (orcid)0000-0003-3143-9270 aut Minna, John D. verfasserin aut Williams, Noelle S. verfasserin (orcid)0000-0003-1894-5742 aut Westover, Kenneth D. verfasserin aut Enthalten in Lung cancer Amsterdam [u.a.] : Elsevier, 1985 153, Seite 73-80 Online-Ressource (DE-627)320649733 (DE-600)2025812-4 (DE-576)264627539 1872-8332 nnns volume:153 pages:73-80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 153 73-80 |
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Liu, Yan @@aut@@ Gao, Galen F. @@aut@@ Minna, John D. @@aut@@ Williams, Noelle S. @@aut@@ Westover, Kenneth D. @@aut@@ |
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Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. 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Loss of wild type |
abstract |
Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. |
abstractGer |
Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. |
abstract_unstemmed |
Objectives: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.Results: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.Conclusions: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted. |
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|
score |
7.400193 |