Expanding the therapeutic applications of PARP inhibitors in cancer by targeting receptor tyrosine kinases.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have revolutionized the treatment of homologous recombination-deficient (HRD) cancers, particularly those with BRCA1/2 mutations. However, their clinical utility is mainly restricted to HRD tumors and also hindered by innate or acquired drug resistance. Consequently, expanding the efficacy of PARPis to HR-proficient tumors represents a major unmet need in cancer therapy. Emerging evidence indicates that receptor tyrosine kinases (RTKs) play critical roles in regulating DNA damage response pathways and HR repair, providing a strong mechanistic rationale for applying their combined inhibition with PARP. Indeed, it has been shown that pharmacological targeting of RTKs can induce an HRD-like or "BRCAness" state, thereby to causing synthetic lethality and sensitizing otherwise resistant tumors to PARPis. This review comprehensively evaluates the mechanistic rationale, preclinical evidence, and clinical progress of PARPi-RTK inhibitor combinations, focusing on RTKs such as EGFR, VEGFRs, c-MET, AXL, ALK, FGFR, IGF1R, and PDGFRs, among others. Preclinical studies demonstrate synergistic effects in multiple cancer types such as ovarian, breast, lung, head and neck, prostate, skin, hepatocellular, and pancreatic malignancies, with early-phase clinical trials showing promise, particularly for VEGFRis combinations. Key molecular mechanisms underlying these synergistic effects include modulation of reactive oxygen species production, PARP activation, HR pathway regulation, cell cycle control, and induction of autophagy and apoptosis. Nevertheless, challenges including drug resistance, toxicity, and heterogeneous clinical responses highlight the need for biomarker-driven patient selection, optimized dosing schedules, and a deeper understanding of tumor-specefic signalings crosstalk.