Abstract 3599: Novel and established acute myeloid leukemia (AML) subsets correlate with ex vivo sensitivity to BCL-2 and PI3K inhibition
Authors: Sumiyoshi Teiko , Bolen Chris , Tyner Jeff , Kurtz Steve , Borate Uma , McWeeney Shannon , Wilmot Beth , Bottomly Dan , Segerdell Erik , Dail Monique , Wilson Timothy R. , Hong Wan-Jen , Venstrom Jeffrey M. 
Published: August 2018

Abstract
Anti-apoptotic BCL-2 family proteins contribute to AML pathogenesis and chemotherapy resistance. Venetoclax (VEN) monotherapy has limited activity in relapsed/refractory AML with a 19% overall response rate. PI3K pathway is constitutively active in 50-80% of AML pts and is tightly linked to the apoptotic pathway. Using clinical, genomic and ex vivo drug sensitivity (IC50) data from 802 AML pts from the multi-institutional Beat AML 1.0 collaboration, we tested the hypothesis that aberrant activation of the PI3K/FLT3 pathway is a mechanism of VEN resistance, with potential utility for identifying pt subsets likely to respond to novel drug combinations. IC50 values were determined by ex vivo drug sensitivity assay, and RNAseq analysis was performed on Illumina HiSeq 2500. To identify pts with activated PI3K signaling, we derived a novel 24-gene expression signature from genes enriched among PIK3CA-mutant tumors, and calculated a PI3K signaling score by applying singular value decomposition to the expression value matrix. Drug response biomarkers were evaluated using a student's t-test without adjustments for multiple comparisons. 45.2% (161/356) of AML pt samples were sensitive to VEN (median IC50, 1.64μM), 70% (190/272) to taselisib (tas), a selective PI3Kα and δ but β-sparing inhibitor (median IC50, 0.06μM) and 95.8% (115/120) to VEN-tas combination (median IC50, 0.02μM). Response to PI3K inhibition varied; 23% (150/659) of AML samples were sensitive to PI3Kδ inhibitor idelalisib (idela; median IC50, 7.23μM) and 63% (337/533) to pan-PI3K inhibitor pictilisib (pic; median IC50, 0.45μM; p=0.03 vs tas). 92% (47/51) of VEN-resistant AML samples tested were sensitive to VEN-tas. VEN sensitivity correlated with high BCL-2 expression, and was greatest among pts with both high BCL-2 and low MCL-1 expression or low PI3K signature. Low expression of PIK3CD (but not PIK3CA/B/G) and the PI3K signature were associated with VEN sensitivity. High BCL-2 expression was associated with resistance to pic, idela and FLT3 inhibitor quizartinib (quiz), with a weaker trend for tas that did not reach statistical significance. Activities of tas, pic and quiz were significantly greater among AML samples with FLT3-ITD mutations, a previously reported VEN resistant subgroup. Expression of activated PI3K signature was higher among AML samples sensitive to pic and quiz. Among 30 AML samples refractory to tas, 18 (60%) were sensitive to VEN and 28 (93%) to VEN-tas. In summary, we identified novel AML subsets characterized by either high gene expression of an activated PI3K gene signature that are refractory to BCL-2 inhibitors or by high BCL-2 expression associated with resistance to PI3K/FLT3 inhibitors. 95.8% of AML pt samples were sensitive to combined inhibition of PI3K and BCL-2. Dual inhibition of PI3K and BCL-2 apoptotic pathways may be a promising combination and should be evaluated in clinical trials.
Citation Format: Teiko Sumiyoshi, Chris Bolen, Jeff Tyner, Steve Kurtz, Uma Borate, Shannon McWeeney, Beth Wilmot, Dan Bottomly, Erik Segerdell, Monique Dail, Timothy R. Wilson, Wan-Jen Hong, Jeffrey M. Venstrom. Novel and established acute myeloid leukemia (AML) subsets correlate with ex vivo sensitivity to BCL-2 and PI3K inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3599.