Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions

Abstract

Intrinsic apoptotic pathway dysregulation plays an essential role in all cancers, particularly hematologic malignancies. This role has led to the development of multiple therapeutic agents targeting this pathway. Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of chronic lymphoid leukemia and acute myeloid leukemia. Given the reported resistance to venetoclax, understanding the mechanisms of resistance and the potential biomarkers of response is crucial to ensure optimal drug usage and improved patient outcomes. Mechanisms of resistance to venetoclax include alterations involving the BH3-binding groove, BCL2 gene mutations affecting venetoclax binding, and activation of alternative anti-apoptotic pathways. Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

Targeting the anti-apoptotic Bcl-2 family proteins: machine learning virtual screening and biological evaluation of new small molecules

“…Molecular docking simulations showed IS21 to bind Bcl-2 protein resembling ABT-199 experimental binding mode. Indeed, IS21 bound conformation was not conformationally affected by G101V, G101A and F104L mutations, among which G101V was reported to be related to ABT-199 resistance, together with mutations involving other residues 27 , 28 . Binding mode inspection revealed IS21 mimicking the four residues of the Beclin 1 BH3 α-helix similarly as reported for ABT-199.…”

“…To some extent, the predicted binding affinities for IS20 and IS21 could also give information of the ligands' propensity to bind the mutated Bcl-2 protein. In particular, based on the associated calculated docking energies, the binding of IS21 would not be affected by the G101V Bcl-2 mutation, reported to be related to resistance to ABT-199 28 . Nonetheless, IS20 docked conformation did not show a unique binding mode.…”

“…These limitations seems to have been overcame with ABT-199 (also known as venetoclax), a potent and selective Bcl-2 binder, approved by the US Food and Drug Administration for the treatment of first-line and relapsed/refractory chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and small lymphocytic lymphoma (SLL) 25 , 26 . Mechanisms of resistance to ABT-199 in CLL patients have been identified in mutations involving several residues, including 101 and 104 27 , 28 . Even if Bcl-2 inhibition represents a promising therapeutic approach for solid tumors, the role of ABT-199 remains to be determined in clinical settings 26 , 29 .…”

Venetoclax plus hypomethylating agent for the salvage treatment of relapsing myeloid malignancies after hematopoietic stem cell transplantation: A multicenter retrospective study on behalf of the Zhejiang Cooperative Group for Blood and Marrow Transplantation

“…Venetoclax (VEN), an oral selective inhibitor of anti-apoptotic protein B-cell leukemia/lymphoma-2 (BCL-2), has been approved for the treatment of a variety of hematologic malignancies. 1,2 In relapsed/ refractory (R/R) myeloid malignancies, the combination of VEN and hypomethylating agent (HMA) has exhibited an encouraging treatment effect. 3 Nevertheless, research about VEN-HMA administration for post-transplant relapse is still in a preliminary stage.…”

“…7 Additionally, patients with IDH1/2 and NPM1 mutations may be sensitive to VEN-based therapy, while patients with NOTCH1, FLT3, and PTPN11 mutations are more likely to be resistant. 1 In the future, the associations between cytogenetic/mutational alterations and VEN response still need to be validated by large-scale prospective studies. E46 CORRESPONDENCE…”