Venetoclax resistance in acute myeloid leukaemia—Clinical and biological insights

Abstract

SummaryVenetoclax, an oral BCL‐2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax is the current standard of care for elderly and patient's ineligible for aggressive therapies. However, venetoclax is being increasingly used with aggressive chemotherapy regimens both in the front line and in the relapse setting. Our growing experience and intensive research demonstrate that certain genetic abnormalities are associated with venetoclax sensitivity, while others with resistance, and that resistance can emerge during treatment leading to disease relapse. In the current review, we provide a summary of the known mechanisms of venetoclax cytotoxicity, both regarding the inhibition of BCL‐2‐mediated apoptosis and its effect on cell metabolism. We describe how these pathways are linked to venetoclax resistance and are associated with specific mutations. Finally, we provide the rationale for novel drug combinations in current and future clinical trials.

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

“…Although venetoclax is an emerging frontline chemotherapeutic in AML, the development of chemoresistant disease limits the drug's clinical efficacy 37,38,39 . In pre-clinical models, the efficacy of venetoclax has been improved by inhibiting respiration (e.g., with IACS) in combination with venetoclax 52,53 .…”

“…Designed to directly initiate the intrinsic pathway of apoptosis at the mitochondria 35 , the targeted therapy venetoclax (i.e., a Bcl-2 inhibitor and a mediator of BAX/BAK dependent apoptosis) was granted regular FDA approval for the treatment of AML in 2020 36 . Despite improving patient outcomes, clinical efficacy of venetoclax remains stifled by the development of chemoresistant disease 37,38,39 . Prior research has established that venetoclax exposure inhibits AML mitochondrial respiration 40 by impinging on components of the electron transport system (ETS) 41 .…”