SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit. Indeed, such CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern and the molecular mechanisms of such resistance remain undefined. Here, we demonstrate that reactivation of mTORC1 signaling through increased expression of the amino acid transporter, SLC36A1, drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms; 1) Rb loss which drives SLC36A1 via reduced suppression of E2f; 2) FXR1 overexpression which promotes SLC36A1 translation and subsequently mTORC1. Finally, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma. Palbociclib (PD) resistant cells (PDR) were generated from 1205Lu cells via sustained treatment with 1uM PD and kept in PD-containing medium. Parental cells were cultured in parallel in standard growth media. Cells were seeded (without drugs) in standard culture media and treated with 1uM PD for 24hours or 8 days