Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis

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Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1–CBX8–GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC. Dual targeting of BRAF and MAPK signaling in the BRAF v600E mutant colorectal cancer patients has shown limited efficacy in clinical studies. Here, the authors identify PLK1 inhibition as synthetic lethal with dual BRAF and EGFR inhibition due to loss of ferroptosis inhibition via a PLK1-CBX8-GPX4 signaling axis in preclinical models of colorectal cancer.

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