PLK1抑制剂onvansertib增强trastuzumab deruxtecan（T-DXd）的抗肿瘤疗效并逆转其在治疗耐药性HER2-low乳腺癌模型中的耐药性

HER2-low tumors represent 55-60% of all breast cancers, of which about 60-70% are hormone receptor-positive (HR+) and the rest triple-negative (TNBC). Most metastatic HER2-low breast cancers become resistant to standard therapies, underscoring the need for improved treatments. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor (TOP1i) payload approved for therapy-resistant metastatic HER2-low breast cancer. Combining T-DXd with agents that potentiate TOP1i activity may enhance its efficacy. Onvansertib, a selective polo-like kinase 1 inhibitor, has shown clinical benefit in combination with the TOP1i irinotecan in metastatic colorectal cancer. Here, we investigated the combination of onvansertib and T-DXd in HER2-low breast cancer models resistant to first-line therapies. The combination was evaluated in eight HER2-low breast cancer cell lines and six patient-derived xenograft (PDX) models, including one TNBC and five HR+ breast cancer models. The TNBC model was derived from a patient who had progressed on chemotherapy and immunotherapy. The HR+ PDXs originated from primary or metastatic tumors and were resistant to fulvestrant and/or CDK4/6 inhibitors. Tumor-bearing nude mice were treated with vehicle, onvansertib (45 mg/kg, orally, five times weekly), T-DXd (4 or 10 mg/kg, intravenously, every three weeks), or the combination and monitored for body-weight changes and tumor growth. The effects of the combination on cell viability, DNA damage and apoptosis were examined in vitro . The combination of onvansertib and T-DXd synergistically inhibited the viability of HER2-low breast cancer cell lines, including fulvestrant and CDK4/6i-resistant cells. In vivo , the combination was well tolerated and showed robust antitumor activity across all PDX models including five models resistant to T-DXd. In the resistant TNBC model and two HR+ models, the combination treatment induced tumor regression in nearly all mice, achieving complete response rates up to 62%. In the one T-DXd-sensitive model, the combination further increased tumor regression and complete responses compared with monotherapies. In the remaining resistant models, the combination enhanced tumor growth inhibition and extended event-free survival relative to single agents. Mechanistically, the combination induced increased and prolonged DNA damage, resulting in higher levels of apoptosis than either single agent alone in HER2-low breast cancer cell lines. Taken together, our data indicate that onvansertib enhances T-DXd's antitumor activity and overcomes resistance through synergistic induction of DNA damage and apoptosis. The findings support the clinical potential of this combination for advanced HER2-low breast cancer resistant to standard-of-care therapies.