2. Academic Validation
  3. PINK1-mediated mitophagy promotes oxidative phosphorylation and redox homeostasis to induce drug-tolerant persister cancer cells

PINK1-mediated mitophagy promotes oxidative phosphorylation and redox homeostasis to induce drug-tolerant persister cancer cells

  • Cancer Res. 2022 Dec 8;CAN-22-2370. doi: 10.1158/0008-5472.CAN-22-2370.
Yun Li 1,  Hengxing Chen 2,  Xuan Xie 3,  Bing Yang 2,  Xiaojuan Wang 1,  Jingyuan Zhang 2,  Tian Qiao 4,  Jiao Guan 5,  Yuntan Qiu 6,  Yong-Xin Huang 7,  Duanqing Tian 1,  Xinyi Yao 6,  Daning Lu 8,  H Phillip Koeffler 9,  Yin Zhang 6,  Dong Yin 6
Affiliations

Affiliations

  • 1 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China.
  • 2 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, GuangZhou, China.
  • 5 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, guangzhou, China.
  • 6 Sun Yat-sen University, Guangzhou, China.
  • 7 Sun Yat-sen University, China.
  • 8 Sun Yat-sen Memorial Hospital, Guangzhou, China.
  • 9 Cedars-Sinai Medical Center, Los Angeles, United States.
PMID: 36480196 DOI: 10.1158/0008-5472.CAN-22-2370
Abstract

The drug-tolerant persister (DTP) state enables Cancer cells to evade cytotoxic stress from anti-cancer therapy. However, the mechanisms governing DTP generation remain poorly understood. Here, we observed that lung adenocarcinoma (LUAD) cells and organoids entered a quiescent DTP state to survive MAPK inhibitor treatment. DTP cells following MAPK inhibition underwent a metabolic switch from glycolysis to Oxidative Phosphorylation (OXPHOS). PTEN-induced kinase 1 (PINK1), a serine/threonine kinase that initiates Mitophagy, was upregulated to maintain mitochondrial homeostasis during DTP generation. PINK1-mediated Mitophagy supported DTP cell survival and contributed to poor prognosis. Mechanistically, MAPK pathway inhibition resulted in MYC-dependent transcriptional upregulation of PINK1, leading to Mitophagy activation. Mitophagy inhibition using either clinically applicable chloroquine or depletion of PINK1 eradicated drug tolerance and allowed complete response to MAPK inhibitors. This study uncovers PINK1-mediated Mitophagy as a novel tumor protective mechanism for DTP generation, providing a therapeutic opportunity to eradicate DTP and achieve complete responses.

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