Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer
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.
|Keywords||Drug resistance, mTOR-targeted therapy, Multi-kinase inhibitor, Polypharmacology, Triple-negative breast cancer (TNBC)|
|Persistent URL||dx.doi.org/10.1007/s10549-019-05380-z, hdl.handle.net/1765/118645|
|Journal||Breast Cancer Research and Treatment|
He, J. (Jichao), McLaughlin, R.P. (Ronan P.), van der Noord, V. (Vera), Foekens, J.A, Martens, J.W.M, van Westen, G. (Gerard), … Van de Water, B. (2019). Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer. Breast Cancer Research and Treatment. doi:10.1007/s10549-019-05380-z