FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells

George M Ramzy; Laura Boschung; Thibaud Koessler; Céline Delucinge-Vivier; Mylène Docquier; Thomas A McKee; Laura Rubbia-Brandt; Patrycja Nowak-Sliwinska

doi:10.3390/cancers14194812

FOLFOXIRI Resistance Induction and Characterization in Human Colorectal Cancer Cells

Cancers (Basel). 2022 Sep 30;14(19):4812. doi: 10.3390/cancers14194812.

Authors

George M Ramzy^{1

2

3}, Laura Boschung^{1

2}, Thibaud Koessler^{3

4}, Céline Delucinge-Vivier⁵, Mylène Docquier^{5

6}, Thomas A McKee⁷, Laura Rubbia-Brandt⁷, Patrycja Nowak-Sliwinska^{1

2

3}

Affiliations

¹ Molecular Pharmacology Group, School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland.
² Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland.
³ Translational Research Center in Oncohaematology, 1211 Geneva, Switzerland.
⁴ Department of Oncology, Geneva University Hospitals, 1205 Geneva, Switzerland.
⁵ iGE3 Genomics Platform, University of Geneva, 1211 Geneva, Switzerland.
⁶ Department of Genetics & Evolution, University of Geneva, 1211 Geneva, Switzerland.
⁷ Division of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva (HUG), 1211 Geneva, Switzerland.

Abstract

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%.

Keywords: FOLFOXIRI; colorectal cancer; drug-resistance.

Grants and funding

The authors acknowledge the funding from the Foundation for the Cancer Fight and Medico-Biological Research, Geneva, Switzerland (to P.N.-S., T.K. and T.A.M.).