ArticleCancer gene therapy2026
mTORC1/2 inhibition induces tumor regression in CDK4/6 inhibitor-insensitive acral melanoma.
Jeremy A Bravo Narula, Kasturee Jagirdar, Sumaiya Begum, Kuai Yu, Meihan Wei, Bailey Roberson, Marie Portuallo, Limin An, Steffanus Hallis, Viviana A Smart and 4 more
Abstract read
In one paragraphArticle in Cancer gene therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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What it found
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2 · The registryThe trial behind it
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3 · Its place in the literatureWho cites it
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4 · The recordCorrections and comments
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5 · Who and what moneyAuthors and funding
14 authors.
Jeremy A Bravo NarulaJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Kasturee JagirdarJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Sumaiya BegumJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.ORCID 0009-0009-7172-2258 Kuai YuJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.ORCID 0009-0007-4788-7429 Meihan WeiJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Bailey RobersonJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Marie PortualloJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Limin AnJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.ORCID 0000-0003-0903-3354 Steffanus HallisJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.ORCID 0000-0002-8841-4835 Viviana A SmartJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.
Manoel O Moraes JuniorJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA.ORCID 0000-0001-6354-1064 Qin LiuThe Wistar Institute; Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA.ORCID 0000-0001-9964-580X Hongkai JiJohns Hopkins Bloomberg School of Public Health; Department of Biostatistics, Baltimore, MD, USA.ORCID 0000-0002-6480-0141 Vito W RebeccaJohns Hopkins Bloomberg School of Public Health; Department of Biochemistry and Molecular Biology, Baltimore, MD, USA. vrebecc2@jh.edu.ORCID 0000-0001-8124-0900 Funding
Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Maureen E. Murphy · 1985 to 2026
$75.9MTRAINING IN AREAS FUNDAMENTAL TO CANCER RESEARCHT32CA009110 · NCI · JOHNS HOPKINS UNIVERSITY · PI MATUNIS, MICHAEL J., WEERARATNA, ASHANI T · 1985 to 2025
$13.1MDissecting clonal diversity in melanoma to overcome therapy resistance andmetastasisK01CA245124 · NCI · JOHNS HOPKINS UNIVERSITY · PI REBECCA, VITO WILLIAM · 2020 to 2024
$595kNCI NIH HHS K01 CA245124NCI NIH HHS P30 CA010815NCI NIH HHS T32 CA009110
6 · The paper itselfAbstract
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
Indexed as
Cyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Mechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MelanomaProtein Kinase InhibitorsAnimalsCell Line, TumorHumansMiceSignal TransductionXenograft Model Antitumor AssaysCDK4 protein, humanCDK6 protein, humanCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Mechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2Protein Kinase Inhibitors
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