Abstract 4536: ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA TG02 is a novel multikinase inhibitor currently in Phase 1 trials for AML and CLL, with a unique spectrum of molecular targets. We have previously shown that TG02 significantly downregulates MCL1 but not BCL2 or BCL2L2 in AML cells at nanomolar concentrations. ABT-737 is a BH3 mimetic which inhibits BCL2, but its effects are impaired in cells which over-express MCL1. Both these agents are documented to target dormant as well as proliferating leukaemia cells and thus have the potential to reduce relapse risk, but cellular responses are heterogeneous. In primary AML samples, BCL-2 expression correlated with that of BCL-XL but not of MCL-1. The response at 48 hours to 100 nM TG02 was measured in primary samples. (This concentration did not inhibit clonogenic growth of haematopoietic stem cells from healthy donors). We show that resistance to TG02 is significantly associated with BCL2 over-expression (P=0.001) but not with MCL1. In CD34+CD38- KG1-a cells, using TG02 with ABT-737 or with the novel and more specific BCL-2 inhibitor ABT-199 at a fixed dose ratio of 1(TG02):20, the combination indices for drug interactions were calculated. For TG02 with ABT-737 and ABT-199 respectively these were IC50 0.59 and 0.26; IC90 0.13 and 0.14, indicating strong synergy, particularly at the IC90. We also show that the OCI-AML-3 cell line, which is resistant to both ABT compounds, was sensitive to TG02 (TG02 IC50 43 nM, IC90 97 nM; ABT-737/199 IC50>4,000nM). All three agents exposed activation-specific epitopes of bax, reduced mitochondrial membrane potential, cleaved caspase 3 and induced phosphatidylserine exposure. 50 nM TG02 + 50 nM ABT199 or ABT-737 was significantly (P<0.05) more toxic than 100 nM of any of the 3 agents individually in a cohort of 12 patient samples treated in vitro for 48 hours. Moreover samples which were sensitive to ABT-199 alone clustered separately from samples sensitive to TG02 alone (p=0.03), indicating that in this heterogeneous disease, the combinatorial approach broadens the range of samples that can be targeted as well as enhancing individual toxicities. We conclude that the cytotoxic actions of TG02 and ABT-737 /ABT-199 are complementary. Citation Format: Amina Abdul-Aziz, Francis Burrows, Ning Yu, Nigel H. Russell, Claire H. Seedhouse, Monica Pallis. ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4536. doi:10.1158/1538-7445.AM2014-4536