KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response

Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear....
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Autor*in:	Xiaohui Shen [verfasserIn] Yuchen Zhang [verfasserIn] Zhuoqing Xu [verfasserIn] Han Gao [verfasserIn] Wenqing Feng [verfasserIn] Wenchang Li [verfasserIn] Yiming Miao [verfasserIn] Zifeng Xu [verfasserIn] Yaping Zong [verfasserIn] Jingkun Zhao [verfasserIn] Aiguo Lu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Übergeordnetes Werk:	In: Cell Death and Disease - Nature Publishing Group, 2010, 13(2022), 4, Seite 13
Übergeordnetes Werk:	volume:13 ; year:2022 ; number:4 ; pages:13

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41419-022-04773-1

Katalog-ID:	DOAJ034353356

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allfields	10.1038/s41419-022-04773-1 doi (DE-627)DOAJ034353356 (DE-599)DOAJb9f36fda430645f69ce266fdc8416eca DE-627 ger DE-627 rakwb eng QH573-671 Xiaohui Shen verfasserin aut KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment. Cytology Yuchen Zhang verfasserin aut Zhuoqing Xu verfasserin aut Han Gao verfasserin aut Wenqing Feng verfasserin aut Wenchang Li verfasserin aut Yiming Miao verfasserin aut Zifeng Xu verfasserin aut Yaping Zong verfasserin aut Jingkun Zhao verfasserin aut Aiguo Lu verfasserin aut In Cell Death and Disease Nature Publishing Group, 2010 13(2022), 4, Seite 13 (DE-627)620145250 (DE-600)2541626-1 20414889 nnns volume:13 year:2022 number:4 pages:13 https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca kostenfrei https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/toc/2041-4889 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 4 13
spelling	10.1038/s41419-022-04773-1 doi (DE-627)DOAJ034353356 (DE-599)DOAJb9f36fda430645f69ce266fdc8416eca DE-627 ger DE-627 rakwb eng QH573-671 Xiaohui Shen verfasserin aut KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment. Cytology Yuchen Zhang verfasserin aut Zhuoqing Xu verfasserin aut Han Gao verfasserin aut Wenqing Feng verfasserin aut Wenchang Li verfasserin aut Yiming Miao verfasserin aut Zifeng Xu verfasserin aut Yaping Zong verfasserin aut Jingkun Zhao verfasserin aut Aiguo Lu verfasserin aut In Cell Death and Disease Nature Publishing Group, 2010 13(2022), 4, Seite 13 (DE-627)620145250 (DE-600)2541626-1 20414889 nnns volume:13 year:2022 number:4 pages:13 https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca kostenfrei https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/toc/2041-4889 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 4 13
allfields_unstemmed	10.1038/s41419-022-04773-1 doi (DE-627)DOAJ034353356 (DE-599)DOAJb9f36fda430645f69ce266fdc8416eca DE-627 ger DE-627 rakwb eng QH573-671 Xiaohui Shen verfasserin aut KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment. Cytology Yuchen Zhang verfasserin aut Zhuoqing Xu verfasserin aut Han Gao verfasserin aut Wenqing Feng verfasserin aut Wenchang Li verfasserin aut Yiming Miao verfasserin aut Zifeng Xu verfasserin aut Yaping Zong verfasserin aut Jingkun Zhao verfasserin aut Aiguo Lu verfasserin aut In Cell Death and Disease Nature Publishing Group, 2010 13(2022), 4, Seite 13 (DE-627)620145250 (DE-600)2541626-1 20414889 nnns volume:13 year:2022 number:4 pages:13 https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca kostenfrei https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/toc/2041-4889 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 4 13
allfieldsGer	10.1038/s41419-022-04773-1 doi (DE-627)DOAJ034353356 (DE-599)DOAJb9f36fda430645f69ce266fdc8416eca DE-627 ger DE-627 rakwb eng QH573-671 Xiaohui Shen verfasserin aut KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment. Cytology Yuchen Zhang verfasserin aut Zhuoqing Xu verfasserin aut Han Gao verfasserin aut Wenqing Feng verfasserin aut Wenchang Li verfasserin aut Yiming Miao verfasserin aut Zifeng Xu verfasserin aut Yaping Zong verfasserin aut Jingkun Zhao verfasserin aut Aiguo Lu verfasserin aut In Cell Death and Disease Nature Publishing Group, 2010 13(2022), 4, Seite 13 (DE-627)620145250 (DE-600)2541626-1 20414889 nnns volume:13 year:2022 number:4 pages:13 https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca kostenfrei https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/toc/2041-4889 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 4 13
allfieldsSound	10.1038/s41419-022-04773-1 doi (DE-627)DOAJ034353356 (DE-599)DOAJb9f36fda430645f69ce266fdc8416eca DE-627 ger DE-627 rakwb eng QH573-671 Xiaohui Shen verfasserin aut KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment. Cytology Yuchen Zhang verfasserin aut Zhuoqing Xu verfasserin aut Han Gao verfasserin aut Wenqing Feng verfasserin aut Wenchang Li verfasserin aut Yiming Miao verfasserin aut Zifeng Xu verfasserin aut Yaping Zong verfasserin aut Jingkun Zhao verfasserin aut Aiguo Lu verfasserin aut In Cell Death and Disease Nature Publishing Group, 2010 13(2022), 4, Seite 13 (DE-627)620145250 (DE-600)2541626-1 20414889 nnns volume:13 year:2022 number:4 pages:13 https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca kostenfrei https://doi.org/10.1038/s41419-022-04773-1 kostenfrei https://doaj.org/toc/2041-4889 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 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_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 4 13
language	English
source	In Cell Death and Disease 13(2022), 4, Seite 13 volume:13 year:2022 number:4 pages:13
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callnumber-first	Q - Science
author	Xiaohui Shen
spellingShingle	Xiaohui Shen misc QH573-671 misc Cytology KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
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topic_title	QH573-671 KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
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title	KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
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title_full	KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
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title_sort	klf5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
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title_auth	KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
abstract	Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment.
abstractGer	Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment.
abstract_unstemmed	Abstract Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment.
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title_short	KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response
url	https://doi.org/10.1038/s41419-022-04773-1 https://doaj.org/article/b9f36fda430645f69ce266fdc8416eca https://doaj.org/toc/2041-4889
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