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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Transport Systems* / genetics
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Amino Acid Transport Systems* / metabolism
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Cell Line, Tumor
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Cyclin-Dependent Kinase 4* / antagonists & inhibitors
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Cyclin-Dependent Kinase 4* / genetics
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Cyclin-Dependent Kinase 4* / metabolism
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Cyclin-Dependent Kinase 6* / antagonists & inhibitors
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Cyclin-Dependent Kinase 6* / genetics
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Cyclin-Dependent Kinase 6* / metabolism
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Drug Resistance, Neoplasm*
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Humans
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Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Melanoma, Experimental* / drug therapy
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Melanoma, Experimental* / genetics
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Melanoma, Experimental* / metabolism
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Melanoma, Experimental* / pathology
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Neoplasm Proteins* / antagonists & inhibitors
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Neoplasm Proteins* / genetics
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Neoplasm Proteins* / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Symporters* / genetics
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Symporters* / metabolism
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Xenograft Model Antitumor Assays
Substances
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Amino Acid Transport Systems
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Neoplasm Proteins
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Protein Kinase Inhibitors
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SLC36A1 protein, human
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Symporters
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Mechanistic Target of Rapamycin Complex 1
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6