Abstract
BackgroundWidely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings.MethodsThe TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3.5-fold cisplatin-resistant subclone HCC38CisR and the 2.1-fold more resistant MDA-MB231CisR. Activation of pro-survival pathways was explored by immunostaining of phospho-receptor tyrosine kinases. Targeted therapies (NVP-AEW541, lapatinib and NVP-BEZ235) against activated pathways were investigated regarding cancer cell growth and cisplatin sensitivity.ResultsIn HCC38CisR and MDA-MB231CisR, phosphorylation of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) was observed. In HCC38CisR, treatment with NVP-AEW541 increased potency of lapatinib almost seven-fold, but both compounds could not restore cisplatin sensitivity. However, the dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 acted synergistically with cisplatin in HCC38CisR and fully restored cisplatin sensitivity. Similarly, NVP-BEZ235 increased cisplatin potency in MDA-MB231CisR. Furthermore, NVP-AEW541 in combination with lapatinib restored cisplatin sensitivity in MDA-MB231CisR.ConclusionSimultaneous inhibition of EGFR and IGF1R in cisplatin-resistant TNBC cell lines was synergistic regarding inhibition of proliferation and induction of apoptosis. Co-treatment with NVP-BEZ235 or with a combination of NVP-AEW541 and lapatinib restored cisplatin sensitivity and may constitute a targeted treatment option for cisplatin-resistant TNBC.
Highlights
Established targeted therapies directed at triple negative breast cancer (TNBC) are missing
Expression and activation of receptor tyrosine kinases (RTKs) was estimated in HCC38, HCC38CisR, and HCC38 exposed to short-term cisplatin stress (6 h Half-maximum inhibitory concentration (IC50) of cisplatin with 24 h or 1 week recovery)
insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) phosphorylation was increased after 6 h cisplatin stress and 24 h recovery, and in HCC38CisR
Summary
Established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Activation of growth factor receptors may play a role in the development of cisplatin resistance in TNBC and due to their involvement in cell proliferation, apoptosis and metastasis they are considered attractive targets for therapies beyond classical chemotherapeutic drugs [9]. Not high expression but high phosphorylation of IGF1R was predictive for poor prognosis in breast cancer [11] Extensive research in this area was done but after initially promising results, phase III clinical trials using anti-IGF1R-targeted therapies were mainly disappointing [12]. These findings might be due to resistance mechanisms like compensatory signaling via growth hormone receptors, insulin receptors or epidermal growth factor receptors. Taking into account that no biomarkers were used to predict response, predictive tools for the use of IGF1R inhibitors might be necessary
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
