Abstract LB275: Reactivation of mitotic arrest upon targeting TACC3 restores immunogenic cell death and T-DM1 response in HER2-positive breast cancer

Abstract Immunogenic cell death (ICD) is a specific form of cell death that is characterized by the release of danger-associated molecular patterns (DAMPs), such as cell surface exposure of calreticulin, ATP and HMGB1 release, and can be induced by several different anti-cancer therapies. This, in turn, evokes a strong anti-tumor immune response, leading to reduced tumor growth. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells, mediated by its payload by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, ICD-related gene signatures correlate with clinical response to T-DM1-containing therapy in pre-treatment samples, and increased infiltration of anti-tumor CD8+ T cells is correlated with better T-DM1 response in post-treatment samples. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. TACC3 inhibition elicits ICD in vivo as shown by vaccination assay. It also potentiates T-DM1 in the human HER2-overexpressing MMTV-huHER2#5 (Fo5) transgenic model by activating ICD markers, release of cytokines and inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance. Citation Format: Ozge Saatci, Mustafa Emre Gedik, Nathaniel Oberholtzer, Meral Uner, Ozge Akbulut, Metin Cetin, Mertkaya Aras, Kubra Ibis, Burcu Caliskan, Erden Banoglu, Stefan Wiemann, Aysegul Uner, Sercan Aksoy, Shikhar Mehrotra, Ozgur Sahin. Reactivation of mitotic arrest upon targeting TACC3 restores immunogenic cell death and T-DM1 response in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB275.