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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• DNA mismatch repair (MMR) corrects DNA alterations and is often deregulated in human cancers.
• MMR-deficient (MMR-d) cancers have high tumor mutational burden (TMB) and microsatellite instability (MSI), making them responsive to checkpoint inhibitor (CPI) immunotherapy.

Purpose of the Study:

• To identify pharmacological strategies to broaden immunotherapy eligibility.
• To discover and characterize a novel small molecule modulator of the MMR pathway.

Main Methods:

• Identification of PMS2 as a druggable target within the MMR pathway.
• In vitro treatment of murine cancer cells with NP1867 to assess MMR abrogation.
• Evaluation of NP1867 effects on TMB, MSI, and mutational signatures.
• In vivo studies in mice using NP1867-pretreated cancer cells to assess CPI sensitivity and tumor response.

Main Results:

• NP1867 effectively abrogates MMR function in vitro, inducing an MMR-d phenotype.
• Pretreatment with NP1867 led to increased TMB, MSI-High status, and MMR-d mutational signatures in cancer cells.
• In vivo, NP1867-treated cancer cells demonstrated enhanced CPI sensitivity, tumor growth delay, and complete responses in mice.

Conclusions:

• Pharmacological targeting of MMR, specifically PMS2, is feasible with novel modulator NP1867.
• This approach can reprogram the tumor microenvironment to enhance immunotherapy response.
• Pharmacological MMR blockade offers a potential strategy to expand the patient population benefiting from CPI immunotherapy.