Pharmacologic Inhibition of PMS2 Induces MMR Deficiency and Response to Immune Checkpoint Blockade.

UNLABELLED: DNA mismatch repair (MMR) detects and corrects postreplicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumor mutational burden (TMB) and microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacologic 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 characterization 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, tumor growth delay, and complete responses. For the first time, we demonstrate pharmacologic targeting of MMR to proactively rewire the tumor-host relationship for therapeutic purposes.

SIGNIFICANCE: We present the discovery and characterization of NP1867, a selective covalent small-molecule inhibitor of MMR protein PMS2. Pharmacologic blockade of PMS2 leads to an MMR-deficient genotype characterized by increased TMB, enriched MMR-d mutational signatures, and MSI-H status. Treatment with NP1867 converts immunoresistant, MMR-proficient cancers into CPI-responsive tumors. See related commentary by Bernards, p. 1486.