biostudies-literatureLopez AU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSPershing Square Sohn Cancer Research Alliance, Irma T. Hirschl TrustNIGMS NIH HHSNew York State Stem Cell Science1199https://www.ebi.ac.uk/biostudies/studies/S-EPMC8901805biostudies-literatureUnknown13(1)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 cancNature communicationsCo-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer.PMC8901805R01 CA178394F31CA2364341S10OD01630P30 CA008748F31 CA2364342R01CA178394DP2 CA174499T32 GM007491P30 CA013330C029154P50 CA140146R01 CA228216U01 CA252048Narayanagari SRReyna DEChi PKopp FNordstrom LUGavathiotis EGitego NVilar EZhou HLopez ATsirigos AMiranda-Roman MAfalseCo-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer.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 canc2022-01-01T00:00:00Z2022 Mar2026-05-31T04:03:32.472Z2025-02-19T01:53:13.009ZS-EPMC89018053525659810.1038/s41467-022-28741-7