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Published on: August 23, 2019
mTORC1/2 inhibition induces tumor regression in CDK4/6 inhibitor-insensitive acral melanoma
Jeremy A Bravo Narula1, Kasturee Jagirdar1, Sumaiya Begum1
1Johns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Abstract:
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.
Insights
Acral melanoma (AM) shows poor response to CDK4/6 inhibitors. Targeting the AKT-mTOR pathway alongside CDK4/6 inhibitors may improve treatment efficacy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Acral melanoma (AM) is an aggressive skin cancer with poor prognosis.
- Current treatments, including CDK4/6 inhibitors (CDK4i/6i), show limited efficacy in AM.
- Frequent pathway alterations in AM suggest underlying resistance mechanisms.
Purpose of the Study:
- To identify mechanisms of resistance to CDK4/6 inhibitors in acral melanoma.
- To investigate the role of AKT-mTOR signaling in CDK4i/6i resistance.
- To evaluate the therapeutic potential of co-targeting CDK4/6 and AKT-mTOR pathways in AM.
Main Methods:
- Utilized a panel of genetically diverse acral melanoma cell lines.
- Administered CDK4/6 inhibitors and assessed downstream signaling.
- Investigated protein-protein interactions between Rb and Sin1.
- Evaluated the efficacy of combined CDK4/6 and AKT-mTOR inhibition.
Main Results:
- CDK4i/6i treatment led to rapid hyperactivation of AKT and mTORC1 signaling.
- CDK4i/6i disrupted the cytoplasmic interaction between Rb and Sin1, a subunit of mTORC2.
- This disruption suggested mTORC2-mediated AKT hyperactivation.
- Combined inhibition of CDK4/6 and AKT-mTOR pathways significantly enhanced anti-cancer effects, including reduced clonogenic survival and increased cytotoxicity.
Conclusions:
- AKT-mTOR signaling acts as a critical escape mechanism in acral melanoma treated with CDK4/6 inhibitors.
- Disruption of the Rb-Sin1 interaction may contribute to AKT pathway hyperactivation.
- Co-targeting CDK4/6 and AKT-mTOR pathways offers a promising therapeutic strategy to improve outcomes in acral melanoma.
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