Dataset Information


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

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.


PROVIDER: S-EPMC6750908 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

| PRJNA450615 | ENA
2018-01-01 | S-EPMC6858088 | BioStudies
2016-01-01 | S-EPMC4873417 | BioStudies
| PRJNA449133 | ENA
2019-01-01 | S-EPMC6731642 | BioStudies
2016-01-01 | S-EPMC5026598 | BioStudies
2017-01-01 | S-EPMC5334447 | BioStudies
2016-01-01 | S-EPMC4794996 | BioStudies
2019-01-01 | S-EPMC7584132 | BioStudies
2019-01-01 | S-EPMC7227487 | BioStudies