Sonrotoclax Overcomes Venetoclax Resistance in Preclinical Hematologic Malignancy Models

Sonrotoclax, a novel selective BCL2 inhibitor, has the potential to overcome BCL2 mutation-induced venetoclax resistance for the treatment of hematologic malignancies, according to a recent study.

The study, published in Blood, was led by Jiuyang Liu, PhD, of BeiGene, Ltd. in Beijing, China, and colleagues. The authors noted the study was driven by drug resistance to venetoclax, the mainstay therapy for relapsed chronic lymphocytic leukemia (CLL).

“Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance.”

That drug resistance is driven by the G101V mutation in BCL2, which is frequently observed in relapsed patients, the authors wrote. This phenomenon has spurred the development of next-generation BCL2 inhibitors to overcome drug resistance.

Sonrotoclax, a next-generation selective BCL2 inhibitor developed by the authors, demonstrates stronger cytotoxic activity and more profound tumor growth inhibition in multiple hematological tumor models compared with venetoclax, according to the paper.

Examining the crystal structures of wild-type BCL2/BCL2G101V in complex with sonrotoclax, the researchers observed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2, which could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutation.

“Sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies, with the potential to overcome BCL2 mutation-induced venetoclax resistance,” the authors wrote.

They added that the therapy is currently under investigation in clinical trials.

Reference

Liu J, Li S, Wang Q, et al. Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy. Blood. 2024. doi:10.1182/blood.2023019706