Bcl-2 pathway inhibition in solid tumors: a review of clinical trials

Abstract

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

Anti‐apoptotic protein BCL‐XL as a therapeutic vulnerability in gastric cancer

“…BCL‐XL plays an important role in cancer pathogenesis and in mediating drug resistance to standard chemotherapy and targeted therapies, which underpins the ongoing clinical trials of combination therapy testing ABT‐263 in solid tumors and lymphoid malignancies 9 . Intriguingly, we only observed subtle activity of ABT‐263 in the BCL‐XL‐dependent GC cell lines (Figure 1A).…”

“…BCL-XL plays an important role in cancer pathogenesis and in mediating drug resistance to standard chemotherapy and targeted therapies, which underpins the ongoing clinical trials of combination therapy testing ABT-263 in solid tumors and lymphoid malignancies. 9 Intriguingly, we only observed subtle activity of ABT-263 in the BCL-XL-dependent GC cell lines (Figure 1A). To understand the low activity of ABT-263 in inhibiting BCL-XL even though it exhibited comparable binding affinity to BCL2, BCL-XL and BCLw in vitro, 16 we compared the ability of A1331852 and ABT-263 to release the proapoptotic initiator of apoptosis, BIM, from its restraint by BCL-XL.…”

“…6,7 Accordingly, pharmacologic inhibitors targeting pro-survival BCL2 proteins have been developed to induce apoptosis in cancer cells. 8,9 Various malignancies show recurrent genetic amplifications affecting pro-survival members of this family, particularly MCL1 and BCL2L1, 10 but there are also studies indicating that BCL2L1 copy number variations (CNVs) are not associated with corresponding expression levels 11 and that BCL2L1 gain/amplification may not exert the same biological function as overexpression. 12 Amplification of BCL2L1 is reported in 11 (10.7%) of the 103 GC cases analyzed by aCGH, while the putative amplification rate of BCL2L1 using the GISTIC algorithm with the TCGA dataset is 2.7% (6/220) (www.cbiop ortal.org).…”

“…In many cancers, the propensity to undergo apoptosis is impaired because of sustained pro‐survival signaling 6,7 . Accordingly, pharmacologic inhibitors targeting pro‐survival BCL2 proteins have been developed to induce apoptosis in cancer cells 8,9 …”

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…Besides the Fas/FasL system, growing evidence reveals connections between other critical proteins of autophagy and apoptosis, which constitute the fundamental mechanisms underpinning their interplay. Through regulating apoptosis, Bcl-2 family proteins play a crucial role in the etiology of cancer [ 214 ]. Bcl-2 transgenic mutations under a B cell-specific immunoglobulin promoter boosted the survival of B and T cells in mice, resulting in splenomegaly, lymphadenopathy, hypergammaglobulinemia, auto-antibody production, and glomerulonephritis [ 215 , 216 , 217 ].…”