Abstract 558: MUC1*-deruxtecan kills tumors that have acquired resistance to trastuzumab containing therapeutics

Abstract Purpose: To develop a treatment for HER2 positive patients whose tumors have stopped responding to Enhertu Methods: HER2 positive BT474 breast cancer cells were induced to become Herceptin resistant (trastuzumab resistant) in vitro via prolonged exposure to sub-lethal levels of the drug. Analysis of the trastuzumab-resistant cells showed that they had greatly increased expression of MUC1*, known to have anti-apoptotic and pro-growth properties. Recall that MUC1* (muk 1 star) is a growth factor receptor created after cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, has already demonstrated safety and cancer selectivity in a 1st-in-human CAR-T clinical trial for treatment of metastatic breast cancers. MNC2 is an IgG1 antibody that only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes. Confocal microscopy and pHrodo show that MNC2 is rapidly and robustly internalized by the cancer cells. We conjugated MNC2 to deruxtecan to yield an MNC2-deruxtecan with a DAR of 7.4. Female NSG mice were xenografted with either BT474-wt cells or the trastuzumab-resistant cells, BT474-Res2. Tumors were allowed to engraft then treated with trastuzumab or MNC2-deruxtecan. Results: Herceptin had little to no effect on BT474-Res2 implanted tumors. However, MNC2-deruxtecan potently killed the trastuzumab resistant tumors in a matter of weeks. MNC2 conjugated to other linker-payloads similarly killed the trastuzumab resistant tumors. Treated animals showed no obvious signs of toxicities. Conclusions: Patients with HER2 positive breast cancers have benefitted greatly from the new ADC Enhertu (fam-trastuzumab deruxtecan). However, most patients, develop resistance to HER2-directed therapies and experience progressive disease leaving them with few treatment options. Here we’ve shown that HER2 positive breast cancer cells acquire resistance to trastuzumab by increasing expression of the powerful growth factor receptor MUC1*. These MUC1*-targeting ADCs offer an effective treatment for these patients. These data support a conclusion that a MUC1*-ADC is safe and could have high therapeutic value for patients who have stopped responding to Enhertu. Citation Format: Cynthia C. Bamdad, Benoit J. Smagghe, Scott T. Moe, Kevin R. Yi, Trevor J. Grant, Mark G. Carter, Daniel S. Miller, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, JacLeen S. Nash, Robert McDermot, Andrew K. Stewart. MUC1*-deruxtecan kills tumors that have acquired resistance to trastuzumab containing therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 558.