Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer.
Breast Cancer Res Treat
; 178(2): 263-274, 2019 Nov.
Article
in En
| MEDLINE
| ID: mdl-31388935
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Resistance, Neoplasm
/
Protein Kinase Inhibitors
/
TOR Serine-Threonine Kinases
/
Triple Negative Breast Neoplasms
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Breast Cancer Res Treat
Year:
2019
Document type:
Article
Affiliation country:
Netherlands