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

Andrea Lopez, Denis E. Reyna, Nadege Gitego, Felix Kopp, Hua Zhou, Miguel A. Miranda-Roman, Lars Ulrik Nordstrøm, Swathi-Rao Narayanagari, Ping Chi, Eduardo Vilar, Aristotelis Tsirigos and Evripidis Gavathiotis ()
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Andrea Lopez: Albert Einstein College of Medicine
Denis E. Reyna: Albert Einstein College of Medicine
Nadege Gitego: Albert Einstein College of Medicine
Felix Kopp: Albert Einstein College of Medicine
Hua Zhou: NYU Langone Health and School of Medicine
Miguel A. Miranda-Roman: Memorial Sloan Kettering Cancer Center
Lars Ulrik Nordstrøm: Albert Einstein College of Medicine
Swathi-Rao Narayanagari: Albert Einstein College of Medicine
Ping Chi: Memorial Sloan Kettering Cancer Center
Eduardo Vilar: The University of Texas MD Anderson Cancer Center
Aristotelis Tsirigos: NYU Langone Health and School of Medicine
Evripidis Gavathiotis: Albert Einstein College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Deregulation 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.

Date: 2022
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DOI: 10.1038/s41467-022-28741-7

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