SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies

Abstract

The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of AML and CLL. However, the response is heterogeneous with 10-50% of newly diagnosed AML patients not responding to HMA and VEN. Furthermore, up to 40% of responding patients relapse shortly. This review discusses the mechanism of action of Venetoclax and the major mechanisms of inherent and acquired resistance to VEN. VEN is highly specific to BCL-2 binding, as such other anti-apoptotic proteins in BCL-2 family induce resistance. These anti-apoptotic proteins can also be upregulated via a number of compensatory cell signaling pathways including PI3K/AKT/mTOR, the MAPK/ERK pathway, and mutant FLT3-ITD. Mutations can occur in BCL-2 and BAX proteins, or they can be silenced by TP53 mutations and other epigenetic changes. Changes to mitochondrial structure and metabolism can induce resistance. Key metabolic regulators include OXPHOS and alternative amino acid metabolism. Finally micro-environmental factors can influence VEN responses. This paper evaluates subsets of AML by differentiation, histology, cytogenetics and molecular markers and their different responses to VEN; with spliceosome mutations, ASXL1, NPM1 and IDH1/2 being favorable while others such as FLT3, TP53 and BCL-2 mutations being less responsive. Currently intensive multi-agent chemotherapy and Venetoclax combinations such as 7+3+VEN are favored in fit younger AML patients. However, with resistant patients' subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance.