Abstract
Acquired resistance to PI3K/mTOR/Akt pathway inhibitors is often associated with compensatory feedback loops involving the activation of oncogenes. Here, we have generated everolimus resistance in ER+ breast cancer cells and in long-term estrogen deprived (LTED) models that mimic progression on anti-estrogens. This allowed us to uncover MYC as a driver of mTOR inhibitor resistance. We demonstrate that both everolimus resistance and acute treatment of everolimus can lead to the upregulation of MYC mRNA, protein expression and, consequently, the enrichment of MYC signatures as revealed by RNA sequencing data. Depletion of MYC resulted in resensitization to everolimus, confirming its functional importance in this setting. Furthermore, ChIP assays demonstrate that MYC upregulation in the everolimus resistant lines is mediated by increased association of the BRD4 transcription factor with the MYC gene. Finally, JQ1, a BRD4 inhibitor combined with everolimus exhibited increased tumor growth inhibition in 3D Matrigel models and an in vivo xenograft model. These data suggest that MYC plays an important role in mediating resistance to everolimus in ER+ and ER+/LTED models. Furthermore, given the regulation ofMYCby BRD4 in this setting, these data have implications for increased therapeutic potential of combining epigenetic agents with mTOR inhibitors to effectively downregulate otherwise difficult to target transcription factors such as MYC.
Highlights
Breast cancer is the most frequent type of cancer diagnosed and is responsible for the second most fatalities in women
To understand and overcome this potential onset of drug resistance, here we describe the generation of everolimus-resistant cell lines both in parental and longterm estrogen-deprived (LTED) backgrounds of ER+ breast cancer cell lines
To generate resistant models, cells were exposed to increasing concentrations of everolimus until growth inhibition in the presence of compound was no greater than 50% (Figure 1A)
Summary
Breast cancer is the most frequent type of cancer diagnosed and is responsible for the second most fatalities in women. Estrogen receptor-positive (ER+) tumors typically rely on circulating estrogen for their growth Given this dependence, treatment options for ER+ breast cancer patients have relied heavily on anti-hormonal strategies with varying anti-estrogen modalities. Treatment options for ER+ breast cancer patients have relied heavily on anti-hormonal strategies with varying anti-estrogen modalities These include such agents as tamoxifen (competes with estrogen for binding to ER) [4], aromatase inhibitors (prevents biosynthesis of estrogen) [5,6,7] and fulvestrant (downregulates ER) [8], all of which have shown success in the clinic. Understanding the molecular mechanisms that drive this resistance is crucial to overcoming these clinical hurdles. To have appropriate biological models in place to help determine molecular drivers of resistance and to test pre-clinical hypotheses
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