Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

Breast Cancer Research and Treatment
Jichao HeBob van de Water

Abstract

Owing to its genetic heterogeneity and acquired resistance, triple-negative breast cancer (TNBC) is not responsive to single-targeted therapy, causing disproportional cancer-related death worldwide. Combined targeted therapy strategies to block interactive oncogenic signaling networks are being explored for effective treatment of the refractory TNBC subtype. A broad kinase inhibitor screen was applied to profile the proliferative responses of TNBC cells, revealing resistance of TNBC cells to inhibition of the mammalian target of rapamycin (mTOR). A systematic drug combination screen was subsequently performed to identify that AEE788, an inhibitor targeting multiple receptor tyrosine kinases (RTKs) EGFR/HER2 and VEGFR, synergizes with selective mTOR inhibitor rapamycin as well as its analogs (rapalogs) temsirolimus and everolimus to inhibit TNBC cell proliferation. The combination treatment with AEE788 and rapalog effectively inhibits phosphorylation of mTOR and 4EBP1, relieves mTOR inhibition-mediated upregulation of cyclin D1, and maintains suppression of AKT and ERK signaling, thereby sensitizing TNBC cells to the rapalogs. siRNA validation of cheminformatics-based predicted AEE788 targets has further revealed the mTOR intera...Continue Reading

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Citations

May 8, 2020·International Journal of Molecular Sciences·Karel Vališ, Petr Novák
Jan 12, 2021·Bulletin du cancer·Weiya CaoDongli Cao
Feb 24, 2021·Pathology, Research and Practice·Junpeng XuMingyang Li
Jul 1, 2021·American Journal of Physiology. Cell Physiology·Kevin M TurnerJun-Lin Guan

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