Abstract 329: PLK1 inhibitor onvansertib potentiates the antitumor efficacy of trastuzumab deruxtecan (T-DXd) and reverses its resistance in therapy-resistant HER2-low breast cancer models.

Abstract 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. Citation Format: Sreeja Sreekumar, Elodie Montaudon, Zeena Eblimit, Migdalia Gonzalez, Davis Klein, Heloise Derrien, Ahmed Dahmani, Tod Smeal, Elisabetta Marangoni, Maya Ridinger. PLK1 inhibitor onvansertib potentiates the antitumor efficacy of trastuzumab deruxtecan (T-DXd) and reverses its resistance in therapy-resistant HER2-low breast cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 329.