Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs

Gremke N, Besong I, Stroh A, von Wichert L, Witt M, Elmshäuser S, Wanzel M, Fromm M, Taudte RV, Schmatloch S, Karn T, Reinisch M, Hirmas N, Loibl S, Wündisch T, Litmeyer AS, Jank P, Denkert C, Griewing S, Wagner U, Stiewe T (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Signal Transduction and Targeted Therapy Springer Nature

Book Volume: 10

Article Number: 92

Journal Issue: 1

DOI: 10.1038/s41392-025-02180-4

Abstract

Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (Her2−) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR+, Her2−, and PIK3CA-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.

Authors with CRIS profile

Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Universitätsklinikum Gießen und Marburg (UKGM) DE Germany (DE) Philipps-Universität Marburg DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Universitätsklinikum Mannheim DE Germany (DE) GBG Forschungs GmbH (German Breast Group) DE Germany (DE)

How to cite

APA:

Gremke, N., Besong, I., Stroh, A., von Wichert, L., Witt, M., Elmshäuser, S.,... Stiewe, T. (2025). Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs. Signal Transduction and Targeted Therapy, 10(1). https://doi.org/10.1038/s41392-025-02180-4

MLA:

Gremke, Niklas, et al. "Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs." Signal Transduction and Targeted Therapy 10.1 (2025).

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