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<p>Breast cancer (BC) is the most prevalent malignancy in women, with hormone receptor-positive, HER2-negative (HR<sup>+</sup>/HER2<sup>−</sup>) tumors representing ~70% of cases. While CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have transformed treatment for metastatic HR<sup>+</sup>/HER2<sup>−</sup> BC, acquired resistance remains a major obstacle. Using HR<sup>+</sup>/HER2<sup>−</sup> BC models with acquired resistance to the CDK4/6 inhibitors Palbociclib or Ribociclib, we uncovered a metabolic vulnerability in highly resistant clones, mediated by mTORC1 hyperactivation and autophagy suppression. Gene expression profiling revealed enrichment of glycolysis and mTORC1 pathways in CDK4/6i-resistant cells, which manifested as heightened sensitivity to the metabolic inhibitors Metformin and Dichloroacetate (DCA). Mechanistically, mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation, as confirmed by LC3 flux assays, leaving resistant cells unable to adapt to energy stress. Treatment with metabolic drugs triggered AMPK activation, ACC inhibition, and PARP cleavage, culminating in apoptosis. Clinically, immunohistochemical analysis of a BC cohort revealed a significant correlation between mTORC1 activity (p4E-BP1<sup>T37/46</sup>) and autophagy suppression (p62 accumulation), supporting the translational relevance of this axis. Our findings propose mTORC1-mediated autophagy defects as a biomarker for metabolic vulnerability in CDK4/6i-resistant BC, offering a rationale for targeting these tumors with metabolic therapies to overcome resistance.</p>

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mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2− breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Luise von Wichert,
  • Alina Stroh,
  • Marie Witt,
  • Michael Wanzel,
  • Marco Mernberger,
  • Sebastian Griewing,
  • Thomas Wündisch,
  • Berit M. Pfitzner,
  • Julia Teply-Szymanski,
  • Anne-Sophie Litmeyer,
  • Carsten Denkert,
  • Uwe Wagner,
  • Thorsten Stiewe,
  • Niklas Gremke

摘要

Breast cancer (BC) is the most prevalent malignancy in women, with hormone receptor-positive, HER2-negative (HR+/HER2−) tumors representing ~70% of cases. While CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have transformed treatment for metastatic HR+/HER2− BC, acquired resistance remains a major obstacle. Using HR+/HER2− BC models with acquired resistance to the CDK4/6 inhibitors Palbociclib or Ribociclib, we uncovered a metabolic vulnerability in highly resistant clones, mediated by mTORC1 hyperactivation and autophagy suppression. Gene expression profiling revealed enrichment of glycolysis and mTORC1 pathways in CDK4/6i-resistant cells, which manifested as heightened sensitivity to the metabolic inhibitors Metformin and Dichloroacetate (DCA). Mechanistically, mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation, as confirmed by LC3 flux assays, leaving resistant cells unable to adapt to energy stress. Treatment with metabolic drugs triggered AMPK activation, ACC inhibition, and PARP cleavage, culminating in apoptosis. Clinically, immunohistochemical analysis of a BC cohort revealed a significant correlation between mTORC1 activity (p4E-BP1T37/46) and autophagy suppression (p62 accumulation), supporting the translational relevance of this axis. Our findings propose mTORC1-mediated autophagy defects as a biomarker for metabolic vulnerability in CDK4/6i-resistant BC, offering a rationale for targeting these tumors with metabolic therapies to overcome resistance.