TY - JOUR
T1 - Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
AU - Lopez, Andrea
AU - Reyna, Denis E.
AU - Gitego, Nadege
AU - Kopp, Felix
AU - Zhou, Hua
AU - Miranda-Roman, Miguel A.
AU - Nordstrøm, Lars Ulrik
AU - Narayanagari, Swathi Rao
AU - Chi, Ping
AU - Vilar, Eduardo
AU - Tsirigos, Aristotelis
AU - Gavathiotis, Evripidis
N1 - Funding Information:
We thank Dr. Thomas J. Ow who generously shared the head and neck cancer cell lines for experimentation. Studies were supported by the Pershing Square Sohn Cancer Research Alliance, an NCI grant 2R01CA178394 and the Irma T. Hirschl Trust Career Award to E.G. NIH grant T32GM007491 and NCI grant F31CA236434 were awarded to A.L. Partial support was also provided by NCI grant P30 CA013330, 1S10OD01630 and a NYSTEM grant no. C029154 to the Einstein Stem Cell Isolation and Xenotransplantation Facility. Cartoons in Figures , , , , and were created with BioRender.com.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-28741-7
DO - 10.1038/s41467-022-28741-7
M3 - Article
C2 - 35256598
AN - SCOPUS:85125971027
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1199
ER -
