PRJNA449133
SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors
The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit of targeting CDK4/6. While suppression of mTORC1 signaling is associated with CDK4/6 inhibition and reactivation of mTORC1 correlates with resistance, the molecular basis of resistance remains undefined. We demonstrate that the amino acid transporter, SLC36A1, drives reactivation of mTORC1, triggering resistance to CDK4/6 inhibitors. Two mechanisms were revealed by Exome and RNA sequencing in CDK4/6 inhibitor-resistant cells; 1) Rb loss drives SLC36A1 expression via reduced suppression of E2f transcription factors which in turn directly regulate SLC36A1 expression; 2) FXR1, an RNA binding protein, overexpression induces SLC36A1 translation by direct binding to SLC36A1 mRNA, which in turn, activates mTORC1, leading activation of CDK/cyclins and reactivation of E2f-dependent transcription. Finally, we demonstrate that a combination of CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma.