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

Akihiro Yoshida1, Yiwen Bu1, Shuo Qie1

  • 1Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.

Science Advances
|September 27, 2019
PubMed

Insights

Reactivation of mTORC1 signaling via SLC36A1 drives resistance to CDK4/6 inhibitors in melanoma. Combining CDK4/6 and mTORC1 inhibitors shows increased therapeutic efficacy in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cyclin-dependent kinase 4/6 (CDK4/6) is dysregulated in melanoma, making it a therapeutic target.
  • CDK4/6 inhibitors show promise but face challenges due to therapy resistance.
  • Molecular mechanisms underlying resistance to CDK4/6 inhibitors are not well-defined.

Purpose of the Study:

  • To investigate the molecular mechanisms of resistance to CDK4/6 inhibitors in melanoma.
  • To identify potential therapeutic strategies to overcome this resistance.

Main Methods:

  • Investigated the role of mammalian target of rapamycin 1 (mTORC1) signaling in CDK4/6 inhibitor resistance.
  • Analyzed the expression and function of the amino acid transporter solute carrier family 36 member 1 (SLC36A1).
  • Examined the impact of Rb loss and fragile X mental retardation syndrome-associated protein 1 (FXRMP1) overexpression on SLC36A1 expression and mTORC1 signaling.
  • Evaluated the therapeutic efficacy of combined CDK4/6 and mTORC1 inhibition in vivo.

Main Results:

  • Reactivation of mTORC1 signaling, driven by increased SLC36A1 expression, promotes resistance to CDK4/6 inhibitors.
  • Increased SLC36A1 expression results from Rb loss (reducing E2f suppression) or FXRMP1 overexpression (enhancing SLC36A1 translation).
  • Combination therapy with CDK4/6 and mTORC1 inhibitors demonstrated enhanced therapeutic efficacy in preclinical models.

Conclusions:

  • mTORC1 reactivation through SLC36A1 is a key mechanism of resistance to CDK4/6 inhibitors in melanoma.
  • Targeting both CDK4/6 and mTORC1 pathways offers a promising strategy for treating aggressive melanoma.
  • Understanding these resistance mechanisms can guide the development of more effective cancer therapies.

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