Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

• DOI: 10.1038/s41467-022-28741-7
• Publication Date: 2022-03-07T11:06:11Z
• Authors: Andrea Lopez; Denis E. Reyna; Nadege Gitego; Felix Kopp; Hua Zhou; Miguel A. Miranda...; Lars Ulrik Nordstrøm; Swathi-Rao Naraya...; Ping Chi; Eduardo Vilar; Aristotelis Tsirigos; Evripidis Gavathi...
• Keywords: 0301 basic medicine; Sulfonamides; Aniline Compounds; Science; Q; bcl-X Protein; Apoptosis; Drug Synergism; Article; 3. Good health; 03 medical and health sciences; Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Humans; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein

AbstractDeregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.