Mechanism of Action Magnifier – 2016 Desk Reference
Venetoclax (ABT-199): a Selective Inhibitor of B-Cell Lymphoma-2
Proteins in the B-cell lymphoma-2 (BCL-2) family are key regulators of apoptosis, and the BCL-2 gene is frequently overexpressed in leukemias and lymphomas.1,2 The BH3-only proteins of the BCL-2 family (ie, those having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (ie, sequestration of the proapoptotic Bcl-2 family members).3
One approach to anticancer treatment has been the development of BH3 mimetic agents, small molecules capable of mimicking BH3-only proteins and thus inhibiting prosurvival proteins and inducing apoptosis in cancer cells.2,3 The first-generation BH3 mimetic navitoclax bound not only to BCL-2 but also to BCL-XL (the physiologic function of which is to protect platelets from apoptosis as they age), and has shown clinical efficacy in some BCL-2–dependent hematologic cancers.2,3 However, thrombocytopenia (a deficiency of platelets in the blood), caused by inhibition of BCL-XL, was observed as a dose-limiting side effect with navitoclax.2,3
Venetoclax, a second-generation BH3 mimetic, is a synthetic derivative of navitoclax that was designed to protect platelets by selectively binding to BCL-2 with high affinity but not to BCL-X.2,3
Venetoclax is a highly potent, orally bioavailable, BCL-2–selective inhibitor designed to block the function of the BCL-2 protein, thereby restoring apoptosis of cancer cells.2,4
Venetoclax mimics BH3-only proteins, the native ligands of Bcl-2 and apoptosis activators, by binding to the hydrophobic groove of Bcl-2 proteins, thereby repressing Bcl-2 activity and restoring apoptotic processes in tumor cells.5 Venetoclax inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets.2
Venetoclax is under investigation in clinical trials for the treatment of patients with various cancer types, including relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, multiple myeloma, and acute myelogenous leukemia.
- Ackler S, Oleksijew A, Chen J, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3:e00178.
- Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202-208.
- Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther. 2013;12:1691-1700.
- The ASCO Post. Venetoclax gaining ground in two types of leukemia. www.ascopost.com/issues/january-25,-2015/venetoclax-gaining-ground-in-two-types-of-leuke mia.aspx. Accessed October 6, 2015.
- Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51:219-227.
ALK Rearrangements in Lung AdenocarcinomaALK has been found to fuse with other partners, leading to potent malignant transformation.1,2 The most common among ALK fusion genes in lung cancer, specifically non–small cell lung cancer (NSCLC), is the EML4 ALK translocation fusion gene (EML4-ALK).1,3-5 The relative prevalence of ALK translocation mutations among [ Read More ]
The clinical application of assays that utilize next-generation sequencing (NGS) technology is accelerating rapidly in the field of oncology.