Abstract
Simple SummaryApoptosis dysergulation is vital to oncogenesis. Efforts to mitigate this cancer hallmark have been ongoing for decades, focused mostly on inhibiting BCL-2, a key anti-apoptosis effector. The approval of venetoclax, a selective BCL-2 inhibitor, for clinical use has been a turning point in the field of oncology. While resulting in impressive improvement in objective outcomes, particularly for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and acute myeloid leukemia, the use of venetoclax has exposed a variety of resistance mechanisms to BCL-2 inhibition. As the field continues to move forward, improved understanding of such mechanisms and the potential biomarkers that could be harnessed to optimize patient selection for therapies that include venetoclax and next-generation BCL-2 inhibitors are gaining increased importance.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.
Highlights
Hematologic malignancies frequently harbor dysregulation in type 1 programmed cell death, known as apoptosis, resulting in a net pro-survival advantage [1]
As venetoclax is highly selective for BCL2, selective pressure leading to activation of other B-cell lymphoma-2 (BCL-2) family members— mantle cell lymphoma (MCL)-1—has been identified as a major mechanism of resistance [54,58,59,60]
Song et al [62] suggested along similar lines that a structural change in the BH3-binding groove is caused by phosphorylation of BCL-2, providing a basis to overcome this resistance of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells by adding kinase inhibitors with venetoclax therapy
Summary
Hematologic malignancies frequently harbor dysregulation in type 1 programmed cell death, known as apoptosis, resulting in a net pro-survival advantage [1]. Anti-apoptotic proteins, BCL-2, are promising therapeutic targets in hematologic malignancies [4]. Efforts to develop targeted BCL-2 therapy in hematologic malignancies have been longstanding [5]. Navitoclax showed efficacy in preclinical trials, thrombocytopenia resulting from inhibition of BCL-XL , a megakaryocyte/platelet pro-survival factor, limited its clinical development [7]. Biomarker studies can support therapy selection by identifying factors that impact sensitivity or resistance to a particular therapeutic option [13,14]. Mutations, and alterations have been identified as possible biomarkers of resistance or response to venetoclax therapy in myeloid malignancies. We discuss the molecular basis of the venetoclax mechanism of action and resistance, and we summarize current data and literature on molecular biomarkers associated with venetoclax response
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