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

## TL;DR

This study identifies a metabolic weakness in breast cancer cells resistant to CDK4/6 inhibitors, offering a new treatment approach.

## Contribution

The study reveals mTOR-driven autophagy suppression as a novel metabolic vulnerability in CDK4/6 inhibitor-resistant breast cancer.

## Key findings

- CDK4/6 inhibitor-resistant breast cancer cells show mTORC1 hyperactivation and autophagy suppression.
- Resistant cells are highly sensitive to metabolic inhibitors like Metformin and DCA.
- mTORC1 activity correlates with autophagy suppression in breast cancer patient samples.

## Abstract

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.