ArticleCancer cell2025
Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer.
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Article in Cancer cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10citing papers in PubMed
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The trial behind it
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Who cites it
10 citing papers in PubMed.
- Mismatch Repair-Proficient Colorectal Cancer Can Evade Immune Surveillance through an Intrinsic Suppressive Program.Cancer discovery · 2026Article
- The DNA damage response and cancer immunotherapy.Nature reviews. Cancer · 2026Review
- Pharmacologic Inhibition of PMS2 Induces MMR Deficiency and Response to Immune Checkpoint Blockade.Cancer discovery · 2026Article
- Universal off-the-shelf TGF-Acta pharmaceutica Sinica. B · 2026Article
- Review
- POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer.bioRxiv : the preprint server for biology · 2026Article
- Acquired High Tumor Mutational Burden and Activity of Immunotherapy after Targeted Therapy in Microsatellite Stable Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Induction Chemotherapy Followed by Immunotherapy Increases Pathological Complete Response Rate in dMMR/MSI-H Gastric Cancer: A Retrospective Cohort Study.ImmunoTargets and therapy · 2026Article
- Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency.NAR cancer · 2025Article
- Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer.Cancer research · 2025Review
Corrections and comments
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Authors and funding
50 authors.
Benoit RousseauDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mitesh PatelDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Oliver ArtzDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Georgios VlachosDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
Shrey PatelDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Omar HayattAntitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Guillem ArgilésDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Michael B FooteDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lingqi LuoDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Boehringer Ingelheim Inc., Ridgefield, CT, USA.
Rachna ShahDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Shub MehtaDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Karthik RangavajhulaDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Caitlin M StewartDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Single-cell Analytics Innovation Lab, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Drew GerberDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Rohini BhattacharyaDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Dennis StephensDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David MielesDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Violaine RandrianDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Somer AbdelfattahDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lin ZhangDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nathalie Membreno-BerganzaDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Michelle F Lamendola-EsselDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Florence Piastra-FaconDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Joana VidalDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medical Oncology, Hospital del Mar Research Institute, Universitat Pompeu Fabra, Barcelona, Spain.
Paul JohannetDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Steve LuDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
James R WhiteResphera Biosciences, Baltimore, MD, USA.
Steven B MaronDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Afsar BarlasMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Caroline M WeipertGuardant Health, Inc., Palo Alto, CA, USA.
Eric RosiekMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Taotao ZhangDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Bing HeDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Sebastien MonetteLaboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, The Rockefeller University, New York, NY, USA.
Rui QuAntitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Deborah FideleAntitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sydney BowkerAntitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Alec KahnDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Pietro Paolo VitielloDepartment of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy; IFOM ETS, The AIRC Institute of Molecular Oncology, Milano, Italy.
Giovanni GermanoIFOM ETS, The AIRC Institute of Molecular Oncology, Milano, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milano, 20133 Milan, Italy.
Alberto BardelliDepartment of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy; IFOM ETS, The AIRC Institute of Molecular Oncology, Milano, Italy.
Rajarsi MandalNorthwell Health, New Hyde Park, NY, USA; Department of Otolaryngology, Hofstra-Northwell School of Medicine, New Hyde Park, NY, USA; The Feinstein Institutes for Medical Research, Manhasset, NY, USA.
Xiaoxiao MaCenter for Immunotherapy and Precision-Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
Tim A ChanCenter for Immunotherapy and Precision-Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; National Center for Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA; Case Western School of Medicine, Cleveland, OH, USA.
Sydney LuDivision of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA.
Andrea CercekDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Omar Abdel-WahabMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Elisa de StanchinaAntitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Neil H SegalDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Luis A DiazDivision of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: diazl5@mskcc.org.
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MGenetic and molecular basis for SRSF2 mutations in myelodysplasiaR01HL128239 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Omar Abdel-Wahab, Robert K Bradley · 2015 to 2026
$8.0MTOWARDS PRECISION IMMUNO-ONCOLOGY: UNRAVELING THE GENOMIC DETERMINANTS AND MECHANISMS UNDERLYING IMMUNOTHERAPY EFFICACY AND RESISTANCER35CA232097 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHAN, TIMOTHY AN-THY · 2018 to 2024
$7.0MInterrogating the minor spliceosome to understand and treat leukemiaR01CA251138 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI ABDEL-WAHAB, OMAR, BRADLEY, ROBERT K · 2020 to 2024
$3.3MTargeting an RNA Binding Protein Network in Acute Myeloid LeukemiaR01CA242020 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI ABDEL-WAHAB, OMAR, AIFANTIS, IANNIS · 2020 to 2024
$2.7MDissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal HematopoiesisK08CA245242 · NCI · STANFORD UNIVERSITY · PI LU, SYDNEY X · 2020 to 2024
$1.2MDefining the role of GNAS in gastrointestinal metastasisK08CA279922 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Michael Foote · 2023 to 2026
$1.1MNCI NIH HHS K08 CA245242NCI NIH HHS K08 CA279922NCI NIH HHS P30 CA008748NCI NIH HHS R01 CA242020NCI NIH HHS R01 CA251138NCI NIH HHS R35 CA232097NHLBI NIH HHS R01 HL128239
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.
Indexed as
Colorectal NeoplasmsDNA Mismatch RepairMutagenesisAnimalsCell Line, TumorCisplatinFemaleGenotypeHumansINDEL MutationMiceMutS Homolog 2 ProteinTemozolomideCisplatinMSH2 protein, humanMutS Homolog 2 ProteinTemozolomidecancerchemotherapyimmune checkpointsimmunogenicitymismatch repairmutagenesisneoantigens
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