Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies
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Cancer Cell International Open Access
REVIEW
Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies XiaoYan Yue†, Qingxiao Chen† and JingSong He*
Abstract Venetoclax has been approved by the United States Food and Drug Administration since 2016 as a monotherapy for treating patients with relapsed/refractory chronic lymphocytic leukemia having 17p deletion. It has led to a breakthrough in the treatment of hematologic malignancies in recent years. However, unfortunately, resistance to venetoclax is inevitable. Multiple studies confirmed that the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family mediated by various mechanisms, such as tumor microenvironment, and the activation of intracellular signaling pathways were the major factors leading to resistance to venetoclax. Therefore, only targeting BCL2 often fails to achieve the expected therapeutic effect. Based on the mechanism of resistance in specific hematologic malignancies, the combination of specific drugs with venetoclax was a clinically optional treatment strategy for overcoming resistance to venetoclax. This study aimed to summarize the possible resistance mechanisms of various hematologic tumors to venetoclax and the corresponding clinical strategies to overcome resistance to venetoclax in hematologic malignancies. Keywords: BCL2, BCL-XL, Combination strategy, Hematologic malignancies, MCL1, Resistance, Venetoclax Background Apoptosis is a form of cell death, which is important in the development of the body, immune responses, and homeostasis. Apoptosis inhibition is also one of the characteristics of tumors, and the induction of apoptosis has become an important strategy for tumor therapy. The apoptotic pathway is regulated by the extrinsic and intrinsic pathways [1, 2]. The intrinsic apoptotic pathway is controlled by B-cell lymphoma-2 (BCL2) family proteins that can regulate the permeability of the outer mitochondrial membrane through protein interactions [3, 4]. The expression of BCL2 family proteins is usually dysregulated in hematologic malignancies [5]. A variety *Correspondence: [email protected] † XiaoYan Yue and Qingxiao Chen are co-first authors Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road, Hangzhou, Zhejiang, China
of tumor cells increased the expression of BCL2 family proteins through multiple mechanisms to ensure cell survival and proliferation, including chromosomal translocation, gene amplification, and downregulation/deletion of microRNAs that degrade BCL2 RNA [6, 7]. For example, BCL2 is usually overexpressed in multiple myeloma (MM) cells with t(11;14) [8]. The deletion of tumor suppressor genes microRNA-15 (miR-15) and microRNA-16 (miR-16) located in the 13q14 chromosome can also lead to increased expression of BCL2 [9, 10]. Therefore, targeting BCL2 can be used as one of the treatment strategies for tumors with high expression of BCL2.
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