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<p>Acral melanoma (AM), a rare and aggressive subtype with 5-year survival rates below 16%, exhibits limited response to CDK4/6 inhibitors (CDK4i/6i) despite frequent pathway alterations. Here, we identify AKT-mTOR signaling as a critical escape mechanism triggered by CDK4/6 inhibition. Using a genetically diverse panel of AM cell lines, we demonstrate that CDK4i/6i induces rapid hyperactivation of AKT (pS473) and mTORC1 (pS6 S240/244) alongside Rb dephosphorylation. Interestingly, CDK4i/6i disrupts the cytoplasmic interaction of Rb with the mTORC2 subunit Sin1, suggesting the loss of the Rb-Sin1 protein-protein interaction may lead to mTORC2-mediated AKT hyperactivation following CDK4i/6i. Pharmacological inhibition of the AKT-mTOR axis significantly increases CDK4i/6i efficacy, as seen in the ability to reduce clonogenic survival and the ability to increase annexin<sup>+</sup> cytotoxicity relative to single-agent CDK4i/6i, AKTi, or mTORi activity alone. These findings provide preclinical rationale for co-targeting CDK4/6 and mTORC1/2 to improve AM outcomes.</p>

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mTORC1/2 inhibition induces tumor regression in CDK4/6 inhibitor-insensitive acral melanoma

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Jeremy A. Bravo Narula,
  • Kasturee Jagirdar,
  • Sumaiya Begum,
  • Kuai Yu,
  • Meihan Wei,
  • Bailey Roberson,
  • Marie Portuallo,
  • Limin An,
  • Steffanus Hallis,
  • Viviana A. Smart,
  • Manoel O. Moraes Junior,
  • Qin Liu,
  • Hongkai Ji,
  • Vito W. Rebecca

摘要

Acral melanoma (AM), a rare and aggressive subtype with 5-year survival rates below 16%, exhibits limited response to CDK4/6 inhibitors (CDK4i/6i) despite frequent pathway alterations. Here, we identify AKT-mTOR signaling as a critical escape mechanism triggered by CDK4/6 inhibition. Using a genetically diverse panel of AM cell lines, we demonstrate that CDK4i/6i induces rapid hyperactivation of AKT (pS473) and mTORC1 (pS6 S240/244) alongside Rb dephosphorylation. Interestingly, CDK4i/6i disrupts the cytoplasmic interaction of Rb with the mTORC2 subunit Sin1, suggesting the loss of the Rb-Sin1 protein-protein interaction may lead to mTORC2-mediated AKT hyperactivation following CDK4i/6i. Pharmacological inhibition of the AKT-mTOR axis significantly increases CDK4i/6i efficacy, as seen in the ability to reduce clonogenic survival and the ability to increase annexin+ cytotoxicity relative to single-agent CDK4i/6i, AKTi, or mTORi activity alone. These findings provide preclinical rationale for co-targeting CDK4/6 and mTORC1/2 to improve AM outcomes.