Development of venetoclax for therapy of lymphoid malignancies

Abstract

B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

Keywords: BCL-2; BCL-xL; MCL-1; chronic lymphocytic leukemia; venetoclax.

Figure 1

Our model for venetoclax resistance and approaches to overcome it by targeting PI3K-mTOR signaling in addition to direct regulation of BCL-xL and MCL-1 levels. Notes: (A) ABT-199 targets BCL-2 in sensitive cells and displaces BIM to cause BAX-mediated apoptosis. (B) As ABT-199 does not target MCL-1 and BCL-xL, these BCL-2 family proteins confer resistance by sequestering BIM that is displaced from BCL-2. (C) NVP-BEZ235 inhibits the PI3K and mTOR pathways, with idelalisib (GS-1101) inhibiting PI3K, both of which interfere with MCL-1 stability, thereby freeing BIM, which then activates BAX, leading to release of cytochrome c and apoptosis (Reproduced from Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e159351). Abbreviations: BCL-2, B-cell lymphoma-2; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin kinase.