Abstract A054: Evaluation of HER3-targeting ADC patritumab deruxtecan in irinotecan-resistant colorectal cancer PDX models reveals resistance mechanisms and informs rational combination strategies

Abstract HER3 (ERBB3), a member of the EGFR family, activates PI3K/AKT signaling through dimerization with other ERBB receptors and is frequently implicated in resistance to targeted therapies. Patritumab deruxtecan (HER3-DXd), a HER3-directed antibody–drug conjugate (ADC), has shown clinical activity in non-small cell lung and breast cancers, urging evaluation in metastatic colorectal cancer (mCRC). Despite frequent HER3 expression in mCRC, its therapeutic relevance in chemotherapy-refractory disease is not well defined. We evaluated HER3-DXd in a panel of 17 molecularly characterized mCRC patient-derived xenograft (PDX) models, the majority of which were derived from patients previously treated with and resistant to irinotecan. Tumor growth inhibition was used to assess response. Molecular profiling (including whole-exome sequencing, RNA sequencing, and Reverse Phase Protein Array) was conducted to elucidate resistance mechanisms and direct rational combination strategies. Single-agent HER3-DXd showed variable activity across models, with limited responses in those exhibiting irinotecan resistance. HER3 expression did not consistently predict response. Molecular analyses revealed persistent PI3K/AKT and MAPK signaling in non-responders, along with upregulated receptor tyrosine kinase (RTK) signaling and a correlation with increased expression of drug efflux transporters. Functional studies demonstrated that combining HER3-DXd with MEK, WEE1, or PLK1 inhibitors produced synergistic antitumor effects. Phospho-proteomic data supported adaptive pathway rewiring following HER3 blockade. These findings highlight the complexity of HER3 signaling in chemotherapy-refractory mCRC and support the development of biomarker-driven combination strategies to enhance therapeutic efficacy of HER3-targeted ADCs (and conceivably other ADCs with topoisomerase inhibitor payload) in this setting. Citation Format: Preeti Kanikarla, Alexey Sorokin, Kelly Gale, Fengqin Gao, Zhensheng Liu, Kanwal Raghav, Scott Kopetz. Evaluation of HER3-targeting ADC patritumab deruxtecan in irinotecan-resistant colorectal cancer PDX models reveals resistance mechanisms and informs rational combination strategies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A054.