1. Academic Validation
  2. BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis

BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis

  • Cell Rep. 2022 Dec 20;41(12):111826. doi: 10.1016/j.celrep.2022.111826.
Vijaya Bharti 1 Reese Watkins 1 Amrendra Kumar 1 Rebecca L Shattuck-Brandt 2 Alexis Mossing 3 Arjun Mittra 4 Chengli Shen 5 Allan Tsung 5 Alexander E Davies 6 Walter Hanel 7 John C Reneau 7 Catherine Chung 1 Gina M Sizemore 3 Ann Richmond 2 Vivian L Weiss 8 Anna E Vilgelm 9
Affiliations

Affiliations

  • 1 Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
  • 2 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 3 The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA.
  • 4 The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Division of Medical Oncology, The Ohio State University, Columbus, OH, USA.
  • 5 Department of Surgery, University of Virginia, Charlottesville, VA, USA.
  • 6 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
  • 7 The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
  • 8 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 9 Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA. Electronic address: [email protected].
Abstract

Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward Apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein Bcl-xL increases the propensity of Cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional precision oncology and omics analyses suggest that Bcl-xL inhibition redirects the outcome of p53 transcriptional response from senescence to Apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a Bcl-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora Kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.

Keywords

Aurora kinase; BAX; BCL-2; BCL-xL; CP: Cancer; p21; p53; patient-derived organoids; senescence; senogenic; senolytic.

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