Navitoclax - CAS 923564-51-6

Despite relative success of therapy for Hodgkin's lymphoma (HL), novel therapeutic agents are needed for patients with refractory or relapsed disease. Recently, anti-PD1 immunotherapy or treatment with the anti-CD30 toxin conjugate brentuximab vedotin (BV) have been associated with remissions; however, the median responses of complete responses (CRs) with the latter were only 6.7 mo. To obtain curative therapy, other effective agents, based on HL biology, would have to be given in combination with BV. Hodgkin's Reed-Sternberg (HRS) cells secrete cytokines including IL-6 and -13, leading to constitutive activation of JAK/STAT signaling. In the present study the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of STAT3 and STAT6 and expression of c-Myc in the HL cell line HDLM-2. These changes were enhanced when, on the basis of a matrix screen of drug combinations, ruxolitinib was combined with the Bcl-2/Bcl-xL inhibitor Navitoclax. The combination augmented expression of Bik, Puma, and Bax, and attenuated Bcl-xL expression and the phosphorylation of Bad.

BACKGROUND: BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-XL are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-XL appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines.

BH3 mimetic compounds induce tumor cell death through targeted inhibition of anti-apoptotic BCL2 proteins. Resistance to one such compound, ABT-737, is due to increased levels of anti-apoptotic MCL1. Using chemical and genetic approaches, we show that resistance to ABT-737 is abrogated by inhibition of the mitochondrial RING E3 ligase, MARCH5. Mechanistically, this is due to increased expression of pro-apoptotic BCL2 family member, NOXA, and is associated with MARCH5 regulation of MCL1 ubiquitylation and stability in a NOXA-dependent manner. MARCH5 expression contributed to an 8-gene signature that correlates with sensitivity to the preclinical BH3 mimetic, navitoclax. Furthermore, we observed a synthetic lethal interaction between MCL1 and MARCH5 in MCL1-dependent breast cancer cells. Our data uncover a novel level at which the BCL2 family is regulated; furthermore, they suggest targeting MARCH5-dependent signaling will be an effective strategy for treatment of BH3 mimetic-resistant tumors, even in the presence of high MCL1.

Unfortunately, the mutagenic activities of chemotherapy and radiotherapy can provoke development of therapy-induced malignancies in cancer survivors. Non-mutagenic anti-cancer therapies may be less likely to trigger subsequent malignant neoplasms. Here we present data regarding the DNA damaging and mutagenic potential of two drugs that antagonize proteins within the Bcl-2 family: ABT-263/Navitoclax and TW-37. Our data reveal that concentrations of these agents that stimulated Bax/Bak-dependent signaling provoked little DNA damage and failed to trigger mutations in surviving cells. The data supplied in this article is related to the research work entitled "Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells" [1].