Abstract
Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines-ACHN and MDA-MB-231-with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors.
Highlights
The PI3K/mTOR pathway performs essential functions for maintaining the malignant phenotype including controlling cell growth, metabolism, and autophagy [1, 2]
The rapamycin analog temsirolimus is approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma and the rapamycin analog everolimus is FDAapproved for the treatment of pancreatic neuroendocrine tumors, renal cell carcinoma, sub-ependymal giant cell astrocytoma associated with tuberous sclerosis, and the treatment of hormone-receptor positive breast cancer
We found an association with epithelial to mesenchymal transition (EMT) and rapamycin resistance on a functional proteomic screen
Summary
The PI3K/mTOR pathway performs essential functions for maintaining the malignant phenotype including controlling cell growth, metabolism, and autophagy [1, 2]. The epithelial to mesenchymal transition (EMT) is defined by the loss of intracellular links along with the gain of migratory and invasive abilities [3] Plasticity exists within this process, allowing cells to transition from epithelial to mesenchymal and resume an epithelial phenotype [4]. Snail and ZEB transcription factors are known EMT drivers, through inducing the crucial step of loss of cell polarity; their www.impactjournals.com/oncotarget expression correlates with time to recurrence and survival in patients with breast carcinoma [3, 5]. MiR-200 has been shown to decrease the expression of ZEB transcription factors to maintain the epithelial phenotype [3, 10,11,12,13,14]. Forced expression of miR200c restores the chemotherapeutic sensitivity of breast cancer cells [15], while loss of miR-200 correlates with increased vimentin expression and decreased E-cadherin expression in breast cancer cells [11, 13, 14]
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