Sensitizing Colorectal Cancer to PARP Inhibitors: Biomarkers, Mechanisms, and Combination Strategies

Poly(ADP-ribose) polymerase inhibitors (PARPis) have transformed the treatment landscape of homologous recombination-deficient malignancies, particularly BRCA1/2-mutant breast, ovarian, pancreatic, and prostate cancers. In contrast, clinical studies evaluating PARPis in broadly selected colorectal cancer (CRC) patients have yielded disappointing outcomes despite evidence that a subset of CRCs harbor DNA damage response (DDR) defects and homologous recombination deficiency (HRD)-associated mutational signatures. These observations highlight the need for improved patient stratification and the development of strategies to enhance PARPi sensitivity in CRC. In this review, we integrate CRC-specific evidence with mechanistic and preclinical findings from other malignancies and discuss candidate biomarkers associated with PARPi responsiveness, including TP53, RAD51, and MRE11, and examine their potential utility in identifying CRC patient populations most likely to benefit from PARP inhibition. We further summarize therapeutic approaches aimed at inducing "BRCAness" and sensitizing CRC cells to PARPis through epigenetic modulation, targeting cell-cycle checkpoint regulators, inhibiting growth factor signaling pathways, and exploiting metabolic vulnerabilities. Emerging strategies involving polyamine inhibition and modulation of NAD+ metabolism have been specifically highlighted for their potential role in therapeutic response. Collectively, these approaches provide a framework for investigating mechanistically compelling opportunities to overcome intrinsic and acquired resistance to PARPis and expand the clinical utility of DDR-targeted therapies in CRC. A deeper mechanistic understanding of PARPi response and resistance, in addition to extensive investigations in CRC-specific models and molecularly selected clinical cohorts, will facilitate the development of biomarker-driven combination therapies and improve outcomes for patients with CRC.