2. Academic Validation
  3. Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

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

  • Nat Commun. 2022 Mar 7;13(1):1199. doi: 10.1038/s41467-022-28741-7.
Andrea Lopez  # 1 2 3,  Denis E Reyna  # 1 2 3,  Nadege Gitego 1 2 3,  Felix Kopp 1,  Hua Zhou 4 5 6,  Miguel A Miranda-Roman 7 8,  Lars Ulrik Nordstrøm 1,  Swathi-Rao Narayanagari 9,  Ping Chi 7 10 11,  Eduardo Vilar 12,  Aristotelis Tsirigos 4 5 6,  Evripidis Gavathiotis 13 14 15
Affiliations

Affiliations

  • 1 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 2 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 3 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 4 Department of Pathology, NYU Langone Health and School of Medicine, New York, NY, USA.
  • 5 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and School of Medicine, New York, NY, USA.
  • 6 Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY, USA.
  • 7 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 10 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 11 Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 12 Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 13 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 14 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • 15 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einsteinmed.edu.
  • # Contributed equally.
PMID: 35256598 DOI: 10.1038/s41467-022-28741-7
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.

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