Abstract 3951: AKT inhibitor capivasertib combines with dexamethasone and venetoclax to enhance anti-tumor responses in the preclinical models of childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common blood cancer of children and the most frequent cause of cancer related death before 20 years of age. Although the survival rate of pediatric patients with ALL is approximately 90% due to innovative chemotherapy regimens, finding treatment options for patients with relapsed/refractory ALL continues to be challenging. The PI3K/AKT/mTOR axis is often constitutively activated in relapse/refractory ALL. For example, loss of the tumor suppressor PTEN leads to hyperactivation of AKT signaling. Despite the importance of PI3K-AKT signaling in ALL, clinically effective treatment strategies to target PI3K-AKT signaling have had limited success. Inhibiting AKT signaling with capivasertib, a first in class pan AKT-inhibitor recently approved for the treatment of ER+ breast cancer, exhibits monotherapy anti-proliferative activity in pediatric T-ALL and B-ALL cell lines. However, only partial anti-proliferative activity was observed from monotherapy capivasertib treatment. To address if the activity of capivasertib in ALL could be improved by combining with other agents, we explored whether addition of the glucocorticoid, dexamethasone, and the Bcl-2 inhibitor, venetoclax could provide better therapeutic benefit in preclinical models of ALL. We conducted a capivasertib centric in vitro combination screen across a panel ALL cell lines. In contrast to monotherapy activities, the combination of capivasertib with dexamethasone and venetoclax showed greater cell killing in 4/5 B-ALL and 3/3 T-ALL cell lines. Interestingly, the combination enhanced antitumoral activity in most ALL cell lines regardless of the presence or absence known PI3K/AKT mutational pathway drivers. Importantly, capivasertib enhanced response to dexamethasone in a subset glucocorticoid refractory ALL cell line models that were insensitive to monotherapy glucocorticoid treatment. To further investigate whether the combination in vitro activity can translate in vivo, combinations of capivasertib, venetoclax and dexamethasone were evaluated in ALL CDX models and a disseminated pediatric PDX of T-ALL harboring known drivers of AKT hyperactivation. Using a clinically relevant dose and schedule of capivasertib, treatment combination groups led to 60% and 70% TGI in the MOLT4 and Karpas-231 xenograft models respectively. Whereas a 20% increase in survival relative to the vehicle group was observed in a disseminated T-ALL PDX model. Taken together, our results provide preclinical evidence for the rational combination of capivasertib, venetoclax and dexamethasone in the treatment of pediatric patients with relapsed/refractory ALL. Citation Format: Brandon Willis, Nadezda Bryan, Justine Roderick-Richardson, Alan Rosen, Lori Chan, Simon T. Barry. AKT inhibitor capivasertib combines with dexamethasone and venetoclax to enhance anti-tumor responses in the preclinical models of childhood acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3951.