SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA450615 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7015710_1.fastq.gz | Fastqsanger.gz | |||
| SRR7015710_2.fastq.gz | Fastqsanger.gz | |||
| SRR7015720_1.fastq.gz | Fastqsanger.gz | |||
| SRR7015720_2.fastq.gz | Fastqsanger.gz | |||
| SRR7015730_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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