Journal Article

Inhibition of CDK 9 enhances AML cell death induced by combined venetoclax and azacitidine

Polin, Lisa A., Dzinic, Sijana H., Ge, Yubin, Yang, Jay, Thibodeau, Jenna, Edwards, Holly, White, Kathryn, Wu, Shuangshuang, Hüttemann, Maik, Gupte, Avanti, Kushner, Juiwanna, Wang, Guan, Wang, Yue, Azmi, Aaban Asfar, Taub, Jeffrey W., Zhao, Jianlei, Liu, Shuang, Boerner, Julie, Yang, Jinli

2025

Overview

Relapsed/refractory (R/R) disease is a major hurdle to long‐term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)‐based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC‐resistant AML cell lines, primary AML patient samples, and patient‐derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c‐MYC and MCL‐1, inducing AraC‐resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two‐drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10‐fold reduction of VEN concentration. The roles of MCL‐1 and c‐MYC in the three‐drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC‐resistant AML by downregulating c‐MYC and MCL‐1 and to a lesser extent cellular respiration.