Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality

Abstract

Metastatic colorectal cancer (mCRC) remains a highly lethal disease because resistance to chemotherapy and targeted agents—including anti-VEGF and anti-EGFR therapies—emerges rapidly and universally. In RAS‑mutant mCRC, second-line treatment with FOLFIRI plus bevacizumab achieves modest clinical benefit, underscoring the need to understand mechanisms of resistance and develop rational combination strategies. Recent evidence implicates oxidative phosphorylation (OXPHOS), antioxidant programs such as the pentose phosphate pathway (PPP), and polo-like kinase 1 (PLK1)–dependent cell‑cycle regulation as key determinants of therapeutic refractoriness. In a recent phase Ib study, onvansertib, a PLK1 inhibitor, combined with FOLFIRI and bevacizumab produced a notable 44% response rate and a median progression-free survival of 12.6 months in RAS‑mutant tumors, suggesting a subset of patients may derive meaningful benefit. Integrating these clinical findings with current metabolic and genomic insights, we highlight how OXPHOS‑driven tumors activate antioxidant networks, sustain chromosome instability, and remodel nutrient usage—features that may blunt synthetic lethality and foster resistance to DNA‑damaging agents, PARP inhibitors, and PLK1 inhibition. We also discuss how altered DNA‑repair reliance (HR, NHEJ, and MMEJ), lactate‑supported mitochondrial metabolism, ENPP1‑mediated immunosuppression, and MYC activation converge to shape chemoresistance and impaired immune responses in microsatellite‑stable colorectal cancer. A more precise therapeutic approach may require selecting patients with combined OXPHOS and PPP activation and leveraging rational combinations involving PLK1, PARP, or ENPP1 inhibitors together with immune checkpoint blockade. Such strategies could enhance the efficacy of ongoing clinical trials and refine future treatment paradigms for heavily pretreated colorectal cancer.