Novel CDK-7 Inhibitor Suppresses Transcription of Oncogenes and Enhances Venetoclax-Mediated Apoptosis in Acute Myeloid Leukemia

Correspondence to: shasan@actrec.gov.in Background: Acute myeloid leukemia (AML) remains a highly fatal disease. Based on the available evidence of deregulated pathways of proliferation and apoptosis in AML, we hypothesize that pharmacological modulation of AML blasts by inhibitors of BCL-2 (Venetoclax) and novel CDK7 inhibitor (CRI-256) will be potently synergistic for the treatment of AML. Materials and Methods: AML cell lines and primary blasts from 50 AML patients were used for antiproliferation assays. Cell proliferation and apoptosis was assessed using flow cytometry and western blotting. CDK7 CRISPR knockout was performed using pSp-Cas9-PURO-CDK7 vector. NOD/SCID mouse models of AML were used to evaluate antileukemic activity of CRI-256. Results: Novel CDK7 inhibitor (CRI-256) downregulated proliferation in leukemic cell lines and in primary AML blast. CRI-256 inhibited the phosphorylation of RNA pol-II leading to decrease in transcription of oncogenes that plays major role in AML proliferation. RNA sequencing data provided further evidence that expression of genes involved in high cell proliferation was downregulated after treatment. Cell cycle arrest as well as induction of apoptosis was detected in dose dependent manner. Significant tumor reduction was observed in AML xenografts after 2 weeks of CRI-256. The antiproliferative data derived from AML cell lines treated with CRI-256 and Venetoclax has shown significant synergism. Conclusion: The data indicated that targeted therapy by novel CDK7 inhibitor induce apoptosis, decrease cell proliferation, and has greater antileukemic activity compared to standard of care in AML. Publication History Article published online: 22 August 2022 © 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India