Abstract SY35-01: Enhancing BH3 mimetic drug induced killing of malignant cells for cancer therapy

Abstract BH3 mimetic drugs are showing great success in the clinic, particularly in hematological cancers. However, p53-mutant hematological cancers remain a major clinical challenge and BH3 mimetic drugs have not shown marked single-agent effects in solid cancers. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of the tumor suppressor p53 (TP53, TRP53), functional p53 is required for maximal cancer cell killing by BH3-mimetic drugs. Here, we report that p53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to further induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. p53-deficient blood cancers lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. Of note, the therapeutic barrier imposed by defects in p53 could be overcome by direct activation of the cGAS/STING pathway in malignant cells. This causes killing of blood cancer cells through p53-independent up-regulation of pro-apoptotic BH3-only proteins. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently killed p53-mutant mouse B lymphoma, human extranodal NK/T lymphoma and human acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle p53-mutant blood cancers, and possibly also other cancers, in the clinic. Citation Format: Sarah T Diepstraten, John E La Marca, Yin Yuan, Fiona C Brown, Andrew W Roberts, Andrew H Wei, Gemma L Kelly, Andreas Strasser. Enhancing BH3 mimetic drug induced killing of malignant cells for cancer therapy [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 SY35-01.