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.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Mice
  • Neoplasms* / drug therapy
  • Precision Medicine
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • bcl-2-Associated X Protein
  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2