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

Autor: John A. Foekens, Gerard J. P. van Westen, Jichao He, Bob van de Water, Vera E. van der Noord, John W.M. Martens, Ronan P. McLaughlin, Yinghui Zhang
Přispěvatelé: Medical Oncology
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Polypharmacology
medicine.medical_treatment
Antineoplastic Agents
Triple Negative Breast Neoplasms
Receptor tyrosine kinase
Targeted therapy
03 medical and health sciences
Preclinical Study
0302 clinical medicine
SDG 3 - Good Health and Well-being
Cell Line
Tumor
medicine
Triple-negative breast cancer (TNBC)
Humans
AEE788
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Protein Kinase Inhibitors
Protein kinase B
Triple-negative breast cancer
PI3K/AKT/mTOR pathway
Cell Proliferation
Everolimus
Dose-Response Relationship
Drug
biology
business.industry
TOR Serine-Threonine Kinases
Multi-kinase inhibitor
Temsirolimus
3. Good health
mTOR-targeted therapy
030104 developmental biology
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Drug resistance
biology.protein
Cancer research
Female
Drug Screening Assays
Antitumor
business
Proto-Oncogene Proteins c-akt
Biomarkers
Signal Transduction
medicine.drug
Zdroj: Breast Cancer Research and Treatment
Breast Cancer Research and Treatment, 178(2), 263-274. Springer New York
Breast Cancer Research and Treatment, 178(2), 263-274
ISSN: 0167-6806
Popis: Purpose 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. Methods 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. Results 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 interactive RPS6K members (RPS6KA3, RPS6KA6, RPS6KB1, and RPS6KL1) as synthetic lethal targets for rapalog combination treatment. Conclusions mTOR signaling is highly activated in TNBC tumors. As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, our results thus provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in TNBC cells. Electronic supplementary material The online version of this article (10.1007/s10549-019-05380-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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