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|Ref Type||Journal Article|
|Authors||Ku BM, Yi SY, Koh J, Bae YH, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ|
|Title||The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma.|
|Date||2016 Mar 22|
|Abstract Text||Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Abemaciclib||Preclinical||Actionable||In a preclinical study, Abemaciclib (LY2835219) reduced RB and AKT activation, and inhibited cell proliferation and colony formation in head and neck squamous cell carcinoma (HNSCC) cell lines in culture, and inhibited tumor growth in HNSCC xenograft models (PMID: 26909611).||26909611|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Abemaciclib + Torin 2||Preclinical||Actionable||In a preclinical study, the combination of Abemaciclib (LY2835219) and Torin2 worked synergistically to reduce viability of head and neck squamous cell carcinoma cells in culture (PMID: 26909611).||26909611|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Abemaciclib + Everolimus||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Abemaciclib (LY2835219) and Afinitor (everolimus) worked synergistically to reduce viability of head and neck squamous cell carcinoma (HNSCC) cells in culture, and to inhibit tumor growth in HNSCC cell line xenograft models, with increased efficacy over either agent alone (PMID: 26909611).||26909611|