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. 2025 Jul 14;43(7):1313-1327.e10.
doi: 10.1016/j.ccell.2025.05.010. Epub 2025 Jun 12.

Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer

Benoit Rousseau  1 , Mitesh Patel  1 , Oliver Artz  1 , Georgios Vlachos  2 , Shrey Patel  1 , Omar Hayatt  3 , Guillem Argilés  1 , Michael B Foote  1 , Lingqi Luo  4 , Rachna Shah  1 , Shub Mehta  1 , Karthik Rangavajhula  1 , Caitlin M Stewart  5 , Drew Gerber  1 , Rohini Bhattacharya  1 , Dennis Stephens  1 , David Mieles  1 , Violaine Randrian  1 , Somer Abdelfattah  1 , Lin Zhang  1 , Nathalie Membreno-Berganza  1 , Michelle F Lamendola-Essel  1 , Florence Piastra-Facon  1 , Joana Vidal  6 , Paul Johannet  1 , Steve Lu  1 , James R White  7 , Steven B Maron  1 , Afsar Barlas  8 , Caroline M Weipert  9 , Eric Rosiek  8 , Taotao Zhang  10 , Bing He  10 , Sebastien Monette  11 , Rui Qu  3 , Deborah Fidele  3 , Sydney Bowker  3 , Alec Kahn  1 , Pietro Paolo Vitiello  12 , Giovanni Germano  13 , Alberto Bardelli  12 , Rajarsi Mandal  14 , Xiaoxiao Ma  15 , Tim A Chan  16 , Sydney Lu  17 , Andrea Cercek  1 , Omar Abdel-Wahab  18 , Elisa de Stanchina  3 , Neil H Segal  1 , Luis A Diaz Jr  19
Affiliations

Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer

Benoit Rousseau et al. Cancer Cell. .

Abstract

Mismatch repair deficient (MMRd) tumors harbor thousands of somatic mutations enriched for insertion-deletion (indels) conferring high sensitivity to immunotherapy. We sought to reproduce this phenotype using mutagenic agents to engineer an MMRd genotype in immunoresistant cells. The combination of temozolomide (TMZ) and cisplatin led to a rapid accumulation of a high mutational load enriched for indels in murine cell lines resulting from the epigenetic loss of Msh2. Pretreated cells showed sensitivity to PD-1 blockade. Systemic treatment with TMZ, cisplatin, and anti-PD-1 bearing immunoresistant tumor cells led to increased survival, intratumoral T cell infiltration, and downregulation of Msh2 expression without affecting healthy tissues. In a clinical trial with 18 patients with refractory mismatch repair proficient colorectal cancer, no responses were seen, but MMRd signatures emerged in cell-free DNA. These findings show that recapitulating an MMRd genotype through chemical mutagenesis can generate an immunogenic phenotype.

Keywords: cancer; chemotherapy; immune checkpoints; immunogenicity; mismatch repair; mutagenesis; neoantigens.

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Conflict of interest statement

Declaration of interests B.R. served in a consulting/advisory role for Neophore LTD and Artios Pharma LTD. B.R. has received travel, accommodations, and expenses from Bayer, Servier, and Astellas outside of the current manuscript. L.L. is currently of Boehringer Ingelheim Inc., CT, USA. J.R.W. is the founder of Resphera Biosciences with equity. J.V. reports personal fees from Merck, Amgen, Sanofi, and Bristol Myers Squibb outside of the current manuscript. G.A. declares Advisor fees from Merus and Gadetta BV, scientific speaking for Amgen. J.V. served in a consulting/advisory role for Pierre-Fabre, MSD, and Merck. J.V. reports travel support and personal fees from Merck, Amgen, Pierre-Fabre, Novartis, and Regeneron outside of the current manuscript. V.R. has received travel, accommodations, and expenses from MSD, Takeda, Amgen, and Merck-Serono and research funding from Servier outside of the current manuscript. M.B.F. has worked on an advisory role for Genzyme, Bristol Meyers Squibb, and Abbott Laboratories. S.B.M. received honoraria from Novartis, Amgen, Elevation Oncology, Pinetree Therapeutics, Purple Oncology, Bolt Biotherapeutics, and Elevation Oncology, financial interest in OneCellDx, research funding from Conquer Cancer Foundation, research travel support from AstraZeneca, and research support from AstraZeneca and Paige.AI. C.M.W is an employee and stockholder of Guardant Health, Inc. T.A.C. acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai. T.A.C. has served as an advisor for Bristol-Myers, MedImmune, Squibb, Illumina, Eisai, AstraZeneca, and Nysnobio. T.A.C. is an inventor on intellectual property and a patent held by MSKCC on using TMB to predict immunotherapy response, which has been licensed to PGDx. A.B. served in a consulting/advisory role for Guardant Health. A.B. received research support by Neophore, AstraZeneca and Boehringer Ingelheim outside of the current manuscript. A.B. is a shareholder of Kither Biotech. A.B. is a member of the scientific advisory board of NeoPhore. G.G. and A.B. are cofounders and shareholders of NeoPhore LTD. A.C. has served as on advisory boards for Amgen, Abbvie, Agenus, Daiichi-Saynko, Merck, GSK, Pfizer, Roche, Janssen, Summit, 3T Biosciences, Urogen, and Regeneron and holds research funding from GKS and Pfizer. A.C holds a pending patent on neoadjuvant PD1 for mismatch repair deficient rectal cancer. O.A.-W. is a founder and scientific advisor of Codify Therapeutics, holds equity, and receives research funding from this company. O.A.-W. has served as a consultant for Amphista Therapeutics and MagnetBio, and is on scientific advisory boards of Envisagenics Inc. and Harmonic Discovery Inc.; O.A.-W. received research funding from Astra Zeneca, Nurix Therapeutics, and Minovia Therapeutics, unrelated to this study. The remaining authors declare no competing interests. N.H.S. has served as a consultant from 3T Biosciences, Regeneron, Pfizer, Agenus, Astellas, Pfizer, Puretech, Novartis, and Numab and received research funding from Roche/Genentech, Pfizer, Merck, BMS, AstraZeneca, Puretech, Immunocore, Regeneron, and Agenus. L.D. is a member of the board of directors of Quest Diagnostics and Epitope. He is a compensated consultant to Innovatus CP, Se’er, Delfi, Blackstone, and Absci. L.D. is an inventor of multiple licensed patents related to technology for ctDNA analyses and mismatch repair deficiency for diagnosis and therapy. Some of these licenses and relationships are associated with equity or royalty payments to the inventors. He holds equity in Quest Diagnostics, Epitope, Se’er, Delfi, and Absci. He divested his equity in Personal Genome Diagnostics to LabCorp in February 2022 and divested his equity in Thrive Earlier Detection to Exact Biosciences in January 2021. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Memorial Sloan Kettering in accordance with their conflict-of-interest policy. B.R., N.H.S., and L.A.D. are inventors of a patent related to this work including the use of temozolomide and cisplatin in combination with immunotherapy (WO2021146266A1). Other authors declared no conflict-of-interest.

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