# Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine

## TL;DR

A CDK9 inhibitor called AZD4573 improves the effectiveness of venetoclax and azacitidine in killing resistant AML cells by reducing c-MYC and MCL-1.

## Contribution

AZD4573 enhances AraC-resistant AML cell death by downregulating c-MYC and MCL-1 when combined with venetoclax and azacitidine.

## Key findings

- AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1 in AraC-resistant AML cells.
- The triple combination of AZD4573, venetoclax, and azacitidine significantly increases AML cell death compared to two-drug combinations.
- The triple therapy spares normal hematopoietic progenitor cells while effectively targeting AML progenitor cells.

## Abstract

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.

The CDK9 inhibitor AZD4573 downregulates c‐MYC and MCL‐1 to induce death of cytarabine (AraC)‐resistant AML cells. This enhances VEN + AZA‐induced cell death significantly more than any combination of two of the three drugs in AraC‐resistant AML cells.