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

Akihiro Yoshida*, Yiwen Bu, Shuo Qie, John Wrangle, E. Ramsay Camp, E. Starr Hazard, Gary Hardiman, Renée de Leeuw, Karen E. Knudsen, J. Alan Diehl

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)
4 Downloads (Pure)

Abstract

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. 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. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome–associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, 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.

Original languageEnglish
Article numbereaax6352
Number of pages15
JournalScience Advances
Volume5
Issue number9
DOIs
Publication statusPublished - 18 Sep 2019

ASJC Scopus subject areas

  • General

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