Abstract 5648: Effects of olverembatinib (HQP1351) in combination with BCL-2 inhibitor lisaftoclax (APG-2575) in T-cell acute lymphoblastic leukemia (T ALL)

Background: T-ALL is a high-risk hematologic cancer arising from malignant transformation of T-cell progenitors, affecting approximately 15% of newly diagnosed pediatric and 25% of adult ALL cases. Survival in children, young adults, and patients with relapsed or refractory disease is poor with limited treatment options. Some T-ALL subtypes depend on pre-TCR/Src signaling and antiapoptotic BCL-2 family proteins for growth and survival. Olverembatinib, a novel multikinase inhibitor, targets oncogenic Src-family kinases (Lck, Fyn, and YES1) essential for T-cell differentiation, survival, and activation. Lisaftoclax is a novel BCL-2 inhibitor under investigation in late-stage clinical trials for multiple hematologic malignancies. Here, we examined the antitumor effects of olverembatinib combined with lisaftoclax in human T-ALL cell lines and explored potential mechanisms of action. Methods: Cellular proliferation was measured using CellTiter-Glo® assays and apoptosis by flow cytometry. Western blotting was used to elucidate potential mechanisms of action. In vivo activity was evaluated using a subcutaneous MOLT4 cell-derived xenograft mouse model. Results: Olverembatinib in combination with lisaftoclax exhibited strong synergistic antiproliferative effects in T-ALL cell lines MOLT4 and Jurkat, with combination indices of 0.2 and 0.1, respectively; apoptosis analyses revealed that the combination significantly increased the percentage of apoptotic cells compared to either agent alone (p < 0.0001). Olverembatinib 10 mg/kg or lisaftoclax 100 mg/kg alone resulted in no or limited tumor inhibition in MOLT4 xenograft model, with treatment-to-control (T/C) values of 113% and 89%, respectively. However, when co-administered, the combination enhanced tumor growth inhibition (T/C, 60%), achieving a synergy index of 1.67. Mechanistically, olverembatinib inhibited Lck activity, and when combined with lisaftoclax, synergistically reduced activity of downstream transcription factor NF-kB p65, leading to downregulation of the key antiapoptotic protein BCL-xL, which is typically upregulated in BCL-2 inhibitor-resistant T-ALL. In addition, the combination downregulated phosphorylation of AKT and GSK3b kinases, resulting in significant degradation of antiapoptotic protein MCL-1 and c-myc, an essential pro-survival oncogene in T-ALL. Increased cleavage of PARP and caspase-3 (markers of apoptosis) was also observed. Conclusions: Olverembatinib in combination with lisaftoclax demonstrated synergistic antitumor effects in T-ALL, providing a scientific rationale for further clinical evaluation of this novel combination therapy in patients with T-ALL. Citation Format: Bo Peng, Yan Xiong, Zhiyan Liang, Ping Min, Huidan Yu, Bingxing Wu, Guoqing Zhai, Zhou Yu, Dajun Yang, Yifan Zhai. Effects of olverembatinib (HQP1351) in combination with BCL-2 inhibitor lisaftoclax (APG-2575) in T-cell acute lymphoblastic leukemia (T-ALL) [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 5648.