FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells

Article Article scientifique Article FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells eng 2022-09-30 2022-09-30 author Ramzy George Mourad 803434 author Boschung Laura 876341 author Kossler Thibaud 0000-0001-9196-9076 500516 author Delucinge Céline 135758 author Docquier Mylene 513819 author Mckee Thomas Alexander 0000-0002-2147-3136 549937 author Rubbia-Brandt Laura 31809 author Nowak-Sliwinska Patrycja 0000-0002-8299-0444 848409 4812 10.3390/cancers14194812 36230735 2072-6694 PMC9564076 FOLFOXIRI, i.e., the combination of folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan, is a first-line treatment for colorectal carcinoma (CRC), yet non-personalized and aggressive. In this study, to mimic the clinical situation of patients diagnosed with advanced CRC and exposed to a chronic treatment with FOLFOXIRI, we have generated the CRC cell clones chronically treated with FOLFOXIRI. A significant loss in sensitivity to FOLFOXIRI was obtained in all four cell lines, compared to their treatment-naïve calls, as shown in 2D cultures and heterotypic 3D co-cultures. Acquired drug resistance induction was observed through morphometric changes in terms of the organization of the actin filament. Bulk RNA sequencing revealed important upregulation of glucose transporter family 5 (GLUT5) in SW620 resistant cell line, while in the LS174T-resistant cell line, a significant downregulation of protein tyrosine phosphatase receptor S (PTPRS) and oxoglutarate dehydrogenase-like gene (OGDHL). This acquired resistance to FOLFOXIRI was overcome with optimized low-dose synergistic drug combinations (ODCs) acting via the Ras-Raf-MEK-ERK pathway. The ODCs inhibited the cell metabolic activity in SW620 and LS174T 3Dcc, respectively by up to 82%. FOLFOXIRI Colorectal cancer Drug-resistance Dewey 615 Dewey 616.07 Dewey 616 Dewey 590 137 Département de pathologie et immunologie 21F 44 Département de génétique et évolution 162 31 Section des sciences pharmaceutiques 17 56 Département de médecine 221 23 Institut de génétique et de génomique 0DH false 476 Lymphomes MALT et réplication virale 807 391 Métastases du foie 657 1325 Pharmacologie moléculaire https://zenodo.org/record/7111566#.Y9FFmoSZOHt Cancers 14 19 1ce33185-412a-49ce-84ba-dcf61b232f71 Article (Published version) Public Article-scientifique-from-europePmc.pdf 4630019 application/pdf CC BY-4.0 22f0272c-d562-4468-991c-8c813eb0d93d Appendix Public cancers-1936952-supplementary.pdf 816484 application/pdf CC BY openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences / Section de biologie / Département de génétique et évolution Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département de médecine Centres et instituts / Institut de génétique et de génomique

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FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells	Cancers			2022	256	189

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Boschung, Laura