Pharmacological inhibition of PMS2 induces MMR deficiency and response to immune checkpoint blockade
DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacological blockade of MMR could broaden the patient population eligible for immunotherapy. Here we reveal MMR protein PMS2 as a druggable target and describe the discovery and characterisation of first-in-class small molecule MMR pathway modulator NP1867. In vitro treatment of murine cancer cells abrogates MMR function and elicits an MMR-d genotype including increased TMB, MMR-d mutational signatures, and MSI-High (MSI- H) status. Inoculation of syngeneic immunocompetent mice with cancer cells pretreated with NP1867 leads to CPI sensitivity, tumour growth delay, and complete responses. For the first time, we demonstrate pharmacological targeting of MMR to proactively rewire the tumour-host relationship for therapeutic purposes.
Authors
- David E. Clark (ORCID: https://orcid.org/0000-0002-3981-1893)
- Paolo Battuello
- Alba Guarné (ORCID: https://orcid.org/0000-0003-4906-9132)
- Martin J. Drysdale (ORCID: https://orcid.org/0000-0002-3847-0556)
- Pietro Paolo Vitiello (ORCID: https://orcid.org/0000-0002-4060-7662)
- Giovanni Germano (ORCID: https://orcid.org/0000-0003-1688-8684)
- Tessa Slater
- Philippe Riou
- Paul C. M. Winship
- Julian Blagg (ORCID: https://orcid.org/0000-0002-7409-0323)
- Alberto Bardelli (ORCID: https://orcid.org/0000-0003-1647-5070)
- Kalpesh Parmar (ORCID: https://orcid.org/0000-0003-3891-4089)
- Eleonora Piumatti
- Ružica Bago
- Alexia Hervieu
- Vito Amodio (ORCID: https://orcid.org/0000-0001-6915-4399)
- Gareth W. Langley (ORCID: https://orcid.org/0000-0003-0875-3712)
- Javier Rodríguez González (ORCID: https://orcid.org/0000-0002-1215-7828)
- M Baker
- Maria T. Rodriguez-Plata (ORCID: https://orcid.org/0009-0008-5046-2410)
- Pradip Patel (ORCID: https://orcid.org/0009-0002-1394-0598)
- Charles Nichols (ORCID: https://orcid.org/0000-0002-2159-371X)
- Adam Peall (ORCID: https://orcid.org/0009-0002-8537-2905)
Institutions
- Charles River Laboratories (Netherlands) (NL)
- University of Milan (IT)
- Charles River Laboratories (United Kingdom) (GB)
- IFOM (IT)
- Charles River Laboratories (United States) (US)
- Department of Medical Sciences (BY)
- Discovery Laboratories (United States) (US)
- Altrincham Hospital (GB)
- Mylan (Switzerland) (CH)
- China Nerin Engineering (China) (CN)
- International University College of Turin (IT)
- McGill University (CA)
- Ahmedabad University (IN)
- University of Turin (IT)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-04-21
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0003
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission