SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors
| Autor: | Akihiro Yoshida, E. Ramsay Camp, Karen E. Knudsen, John Wrangle, Shuo Qie, Renée de Leeuw, J. Alan Diehl, Yiwen Bu, E. Starr Hazard, Gary Hardiman |
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| Rok vydání: | 2019 |
| Předmět: |
endocrine system diseases
Amino Acid Transport Systems Melanoma Experimental mTORC1 Mechanistic Target of Rapamycin Complex 1 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Cyclin-dependent kinase Cell Line Tumor Humans Medicine Amino acid transporter General E2F neoplasms Protein Kinase Inhibitors Research Articles Cancer 030304 developmental biology 0303 health sciences Multidisciplinary integumentary system Symporters biology business.industry Kinase Melanoma SciAdv r-articles Cyclin-Dependent Kinase 4 Translation (biology) Cell Biology Cyclin-Dependent Kinase 6 medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins 3. Good health Solute carrier family Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research biology.protein biological phenomena cell phenomena and immunity business Research Article Signal Transduction |
| Zdroj: | Yoshida, A, Bu, Y, Qie, S, Wrangle, J, Camp, E R, Hazard, E S, Hardiman, G, de Leeuw, R, Knudsen, K E & Diehl, J A 2019, ' SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors ', Science Advances, vol. 5, no. 9, eaax6352 . https://doi.org/10.1126/sciadv.aax6352 Science Advances |
| ISSN: | 2375-2548 |
| Popis: | We identified unique molecular mechanisms of resistance to CDK4/6 inhibitors, an area of intense biomedical investigation. 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. |
| Databáze: | OpenAIRE |
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