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

doi:10.1126/sciadv.aax6352

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

Sci Adv. 2019 Sep 18;5(9):eaax6352. doi: 10.1126/sciadv.aax6352. eCollection 2019 Sep.

Authors

Akihiro Yoshida¹, Yiwen Bu¹, Shuo Qie¹, John Wrangle², E Ramsay Camp³, E Starr Hazard⁴, Gary Hardiman^{2

4}, Renée de Leeuw⁵, Karen E Knudsen⁵, J Alan Diehl¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
² Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
³ Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
⁴ Center for Genomic Medicine Bioinformatics, Medical University of South Carolina, Charleston, SC 29425, USA.
⁵ Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport Systems* / genetics
Amino Acid Transport Systems* / metabolism
Cell Line, Tumor
Cyclin-Dependent Kinase 4* / antagonists & inhibitors
Cyclin-Dependent Kinase 4* / genetics
Cyclin-Dependent Kinase 4* / metabolism
Cyclin-Dependent Kinase 6* / antagonists & inhibitors
Cyclin-Dependent Kinase 6* / genetics
Cyclin-Dependent Kinase 6* / metabolism
Drug Resistance, Neoplasm*
Humans
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Melanoma, Experimental* / drug therapy
Melanoma, Experimental* / genetics
Melanoma, Experimental* / metabolism
Melanoma, Experimental* / pathology
Neoplasm Proteins* / antagonists & inhibitors
Neoplasm Proteins* / genetics
Neoplasm Proteins* / metabolism
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects*
Signal Transduction / genetics
Symporters* / genetics
Symporters* / metabolism
Xenograft Model Antitumor Assays

Substances

Amino Acid Transport Systems
Neoplasm Proteins
Protein Kinase Inhibitors
SLC36A1 protein, human
Symporters
Mechanistic Target of Rapamycin Complex 1
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6

Abstract

Publication types

MeSH terms

Substances

Grants and funding