Mitophagy is a novel protective mechanism for drug-tolerant persister (DTP) cancer cells

Autophagy. 2023 Sep;19(9):2618-2619. doi: 10.1080/15548627.2023.2177398. Epub 2023 Feb 15.

Abstract

Drug-tolerant persister (DTP) cancer cells drive residual tumor and relapse. However, the mechanisms underlying DTP state development are largely unexplored. In a recent study, we determined that PINK1-mediated mitophagy favors DTP generation in the context of MAPK inhibition therapy. DTP cells that persist in the presence of a MAPK inhibitor exhibit mitochondriadependent metabolism. During DTP state development, MYC depletion alleviates the transcriptional repression of PINK1, resulting in PINK1 upregulation and mitophagy activation. PINK1-mediated mitophagy is essential for mitochondrial homeostasis in DTP cells. Either knockdown of PINK1 or inhibition of mitophagy eradicates DTP cells and achieves complete responses to MAPK inhibition therapy. This study reveals a novel role of mitophagy as a protective mechanism for DTP development.

Keywords: Drug-tolerant persister; MAPK inhibitor; PINK1; mitophagy; quiescent cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Autophagy
  • Cell Line, Tumor
  • Mitochondria / metabolism
  • Mitophagy*
  • Neoplasms* / metabolism
  • Protein Kinases / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Protein Kinases
  • Ubiquitin-Protein Ligases

Grants and funding

This work was supported by the National Key Research and Development Program of China [2021YFA0909300]; China Postdoctoral Science Foundation [2022M713588]; Guangdong Science and Technology Department [2019B020226003, 2021A0505030084]; Guangdong Science and Technology Department [2020B1212060018, 2020B1212030004]; National Natural Science Foundation of China [82102716]; National Natural Science Foundation of China [82073067, 81872140, 81621004, 81420108026].