The intersection of homologous recombination (HR) and mismatch repair (MMR) pathways in DNA repair-defective tumors

Abstract

Homologous recombination (HR) and mismatch repair (MMR) defects are driver mutational imprints and actionable biomarkers in DNA repair-defective tumors. Although usually thought as mutually exclusive pathways, recent preclinical and clinical research provide preliminary evidence of a functional crosslink and crosstalk between HRR and MMR. Shared core proteins are identified as key players in both pathways, broadening the concept of DNA repair mechanism exclusivity in specific tumor types. These observations may result in unexplored forms of synthetic lethality or hypermutable tumor phenotypes, potentially impacting the cancer risk management, and considerably expanding in the future the therapeutic window for DNA repair-defective tumors.

Fig. 1. HRD- and MMRd-associated tumors.

Classically, breast, ovarian, pancreatic, and prostate hereditary cancers are known as HRD tumors; while, colorectal and endometrium, but also additional cancers, including cancers of the stomach and renal pelvis, are classified as MMRd-associated tumors. Determination of MSI/MMRd as well as HRD status in different cancer types, beyond their characteristic mutational footprints, may improve genetic screening strategies and treatment stratification (Created with BioRender.com).

Fig. 2. The link between MMR and HRR.

Emerging studies highlight potential interactions of mechanisms that underly different forms of DNA repair, such as MMR and HRR. Shared core proteins, including RPA, EXO1, RFC, MSH2/3, MLH3, and PMS2, are identified as key players in both pathways, broadening the concept of DNA repair mechanism exclusivity in specific tumor types (Created with BioRender.com).