Abstract SY35-03: Targeting apoptosis to overcome cancer chemoresistance in solid tumors

Abstract Despite major advances in cancer therapy, intrinsic and acquired chemoresistance remains the primary obstacle to achieving durable clinical responses. While cytotoxic and targeted agents as well as immunotherapies aim to induce apoptosis in cancer cells, their efficacy is often undermined by the upregulation of pro-survival BCL-2 family proteins - a central mechanism of resistance and hallmark of cancer. To identify effective strategies to overcome chemoresistance, we systematically measured apoptotic dependencies using BH3 profiling, CRISPR, and small molecule screening across hundreds of diverse cancer cell lines and primary specimens. We found that nearly all tumor cells from solid cancers rely on both BCL-XL and MCL-1 for survival. However, inhibition of either protein alone induces only modest cell death due to rapid apoptotic adaptation (RAA) - a compensatory upregulation of both the targeted and alternative pro-survival proteins - which we find can be driven by activation of heat shock protein 27 (HSP27). HSP27 inhibition forestalls RAA and enhances apoptosis driven by single-agent BH3 mimetics in cancer cells. Furthermore, we find that simultaneous targeting of BCL-XL and MCL-1 triggers robust and synergistic apoptosis in vitro across nearly all solid cancers, yet this approach is not clinically viable due to severe in vivo toxicity. To circumvent this, we screened for agents that can indirectly modulate expression of these proteins and found that paclitaxel treatment selectively depletes MCL-1 and upregulates BCL-XL, creating a state of apoptotic convergence in which BCL-XL is forced to sequester crucial pro-apoptotic proteins (BIM, BAX, BAK) during mitotic arrest. In this context, BCL-XL inhibition triggers synergistic apoptosis even in chemoresistant cells. Utilizing chemoresistant ovarian cancer cell line and patient-derived xenograft (PDX) models, we find that the platelet-sparing BCL-XL-targeting PROTAC, DT2216, when combined with paclitaxel, achieves complete eradication of xenograft tumors in multiple models. This was achieved without overt toxicity - a result unattainable with either agent alone or with conventional BCL-XL inhibitors due to dose-limiting thrombocytopenia. Notably, DT2216 also reduces the RAA that is evident with conventional BCL-XL inhibitors, indicating that targeted degradation of pro-survival proteins will produce more durable therapeutic responses than inhibition alone. Collectively, these findings provide a mechanistic and translational framework for safely and effectively co-targeting MCL-1 and BCL-XL in solid tumors and support the clinical development of BCL-XL-targeting PROTACs as a promising strategy to overcome chemoresistance in ovarian cancer and other solid tumors. Citation Format: Kristopher A. Sarosiek. Targeting apoptosis to overcome cancer chemoresistance in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY35-03.