The CDK-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle in estrogen receptor (ER)-positive breast cancer. Several small-molecule inhibitors of CDK4/6 (abemaciclib, ribociclib, and palbociclib) have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors.1 mTOR inhibitors have also shown potential in clinical trials in this disease setting.2 Recent data have suggested cooperation between the PI3K pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated.3
In their presentation at SABCS 2017, the authors showed that profound and durable inhibition of ER-positive breast cancer growth is likely to require multiple hits on E2F-mediated transcription.4 They demonstrated that inhibition of mTOR using the mTORC1/2 inhibitor vistusertib at 300 nM causes a >50% decrease in cyclin D1 protein levels and RB phosphorylation in 3 cell lines. At these concentrations, vistusertib treatment also elicits marked effects on E2F-mediated transcription, causing changes in the mRNA levels of 28 of 43 (65%) of a selected set of E2F target genes. Combined inhibition of mTOR, CDK4/6, and ER delivers profound and durable regressions in breast cancer cell lines and xenografts (110.2% tumor growth inhibition at day 48). In vivo data showed that over a period of 58 days, tumors failed to regrow in the presence of the triplet combination compared with either agent alone, suggesting the triplet is necessary to maintain growth inhibition. Furthermore, they showed that CDK4/6 inhibitor‒resistant cell lines reactivate the CDK-RB-E2F pathway, but remain sensitive to mTOR inhibition (EC50 52.7 nM in parental cells vs 39.6-73.3 nM in a number of palbociclib-resistant cell populations), suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed with CDK4/6 inhibitor therapy.
On the strength of these data, a phase 1/2 multicenter study (PASTOR) combining the dual TOR kinase inhibitor vistusertib with palbociclib and fulvestrant is underway to explore the safety and efficacy of the triplet combination in patients with metastatic breast cancer.