IL-2:IL-15 : implications for cancer therapy

Division Of Clinical Sciences - Nci

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Abstract

To investigate previously undescribed therapeutic targets in ATL, we performed a genome-wide clustered regularly, interspaced short palindromic repeat (CRISPR)-Cas9 screening to identify genetic vulnerabilities in ATL cells. CDK6 (cyclin dependent kinase 6) was the best scoring gene. This prompted us to focus on CDK6 as a therapeutic molecular target in ATL. Two sgRNAs targeting the coding sequence of CDK6 exhibited strong cytotoxicity for all of 5 ATL cell lines tested. The sgCDK6 mediated toxicity was mediated by G1 cell arrest and in part by apoptosis, and successfully rescued by retroviral induction of sgRNA resistant CDK6 cDNA in two ATL cell lines tested. Given that CDK6 was discovered as the best valuable target in ATL cells among 19,144 genes, we extended our analysis to evaluate pharmacological inhibition of CDK6 in ATL cells. Palbociclib, FDA approved CDK4/6 inhibitor was toxic in 11 ATL cell lines and in 4 primary ATL cells. However, CDK4/6 inhibition stimulates glycolytic and oxidative metabolism and is associated with an increase in mTOR activity. The combination of palbociclib and the mTOR inhibitor AZD-8055 and everolimus showed antiproliferative activity against a series of ATL cell lines, primary ATL cells and patient PBMCs. Furthermore, the combination of palbociclib with mTOR inhibitors showed additive antiproliferative activity in increasing the survival of mice with the 43Tb(-) model of ATL. These studies support initiation of our clinical trial of palbociclib with the mTOR1/2 inhibitor sapanisertib for patients with T-cell malignancies including HTLV-1 associated severe chronic, acute, and lymphomatous ATL. Our study demonstrates new therapeutic targets for ATL, and we propose CDK6 inhibition with CDK4/6 inhibitor palbociclib with an mTOR1/2 inhibitor for future clinical trials. Work on this project was discontinued in FY22