ARTS mimetic (AM) small molecules enhance the killing effect of BH3 mimetic ABT-199 (Venclexta®) by degrading Bcl-2 and overcomes resistance to the drug

Bcl-2 (B-cell lymphoma 2) protein is a potent inhibitor of apoptosis which is highly expressed in many types of cancers. Therefore, Bcl-2 became a major target for developing anti-cancer drugs. ABT-199 (Venclexta®) is a recently FDA-approved drug used for treatment of CLL (Chronic Lymphocytic Leukemia) patients. ABT-199 acts by binding to Bcl-2 and neutralizing its anti-apoptotic effect. ARTS is a pro-apoptotic protein that promotes apoptosis by binding and degrading Bcl-2 through Ubiquitin-Proteasome-System (UPS). ARTS brings Bcl-2 into close proximity with X-linked inhibitor of apoptosis protein (XIAP) which acts as an E3 ligase that can ubiquitylate and degrade Bcl-2. Our lab has identified ARTS-mimetic (AM) small molecules, which induce apoptosis by binding XIAP and promoting the degradation of both Bcl-2 and XIAP itself. We have found that ABT-199 induces upregulation of Bcl-2 levels in several cancer cell lines. One of the major challenges in using ABT199, is that patients develop resistance to the drug following prolonged treatment. We used A375 melanoma cells, which are resistant to ABT199.

We found that treatment with ABT-199 alone resulted in increased levels of BCL-2, and combined treatment with B3 reduced BCL-2 levels leading to enhanced apoptosis. We found that this effect is due to increased binding between XIAP and BCL-2 with Bx treatment, which in turn can promote enhanced BCL-2 degradation by XIAP. Thus, combined treatment of ABT-199 and Bx in melanoma A375 cells overcomes their resistance to ABT-199. Our results provide an alternative and complementary approach to treatment of cancers resistant to ABT-199