Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

Abstract

Abstract. Everolimus (RAD001) is an inhibitor of mammalian target of rapamycin used in combination with exemestane to treat hormone receptor-positive advanced breast cancer. However, not all patients are equally sensitive to RAD001 and certain patients develop resistance. Therefore, the present study analyzed the mechanisms involved in the resistance of breast cancer cells to RAD001 in order to identify a potential tool to overcome it. The effects of RAD001 on the inhibition of cell viability, on the induction of apoptosis and autophagy and on the regulation of survivin, an anti-apoptotic protein, were evaluated in two breast cancer cell lines: BT474 (luminal B) and MCF7 (luminal A). RAD001 was demonstrated to induce autophagy in the two cell lines at following a short period of treatment (4 h) and to induce apoptosis exclusively in BT474 cells following longer periods of treatment (48 h). RAD001 induced the downregulation of survivin in BT474 cells and its upregulation in MCF7 cells. Consequently, inhibiting survivin with YM155 resulted in the acquired resistance of MCF7 cells to RAD001 being reverted, restoring RAD001-induced apoptosis. These data demonstrated that RAD001 exerted anti-proliferative and pro-apoptotic effects on breast cancer cells, but that these effects were repressed by the simultaneous up-regulation of survivin. Finally, the results demonstrated that inhibiting the expression of survivin resulted in the restoration of the anti-neoplastic activity of RAD001.

Genes and proteins associated with chemotherapeutic resistance in breast cancer

“…These data reinforce the hypothesis that survivin is a mediator of resistance to chemotherapy and it is suggested that the increase of this protein in cancer tissues is an unfavorable prognostic marker, which is associated with an increased risk of recurrence [25].…”

“…The positive regulation of survivin contributes to establish resistance to taxanes, kinesin inhibitors and mTOR inhibitors in breast cancer cells, this has been demonstrated by performing survivin inhibition assays in samples resistant to chemotherapy and inducing the anticancer activity of these drugs, and it was found that by suppressing the activity of survivin, chemotherapy provides good results [25].…”

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

“…Recently, in BC cells, survivin, a downstream target of the PI3K/AKT/mTOR pathway, was demonstrated to be involved in drug resistance, especially to taxanes and kinesin inhibitors [31]. Taglieri and colleagues investigated whether survivin was involved in the acquired resistance to everolimus treatment in hormone-sensitive breast tumors, showing that the drug is able to modify survivin expression in vitro in opposite ways with a downregulation in the sensitive cells and an upregulation in the resistant ones [32]. Moreover, the block of survivin upregulation in these cells restored sensitivity to everolimus, suggesting that survivin is a potential target for future treatments [32].…”

“…Taglieri and colleagues investigated whether survivin was involved in the acquired resistance to everolimus treatment in hormone-sensitive breast tumors, showing that the drug is able to modify survivin expression in vitro in opposite ways with a downregulation in the sensitive cells and an upregulation in the resistant ones [32]. Moreover, the block of survivin upregulation in these cells restored sensitivity to everolimus, suggesting that survivin is a potential target for future treatments [32]. The acquired resistance to mTORC1 inhibitors was attributed to compensatory feedback loops involving the activation of oncogenes such as Myc , the upregulation of which is mediated by the transcriptional regulator bromodomain-containing protein 4 (BRD4) [33].…”

Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer

“…Aromatase inhibitor based monotherapy is frequently combined with selective small molecule inhibitors of CDK4/6 and mTOR pathways. Long-term treatment involving single agent therapy or multi-agent combination therapy is frequently associated with acquired drug resistance predominantly due to the emergence of cancer stem cells, thereby impacting therapeutic efficacy and promoting disease progression (3)(4)(5).…”