FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Douglas D Fang; Hengrui Zhu; Qiuqiong Tang; Guangfeng Wang; Ping Min; Qixin Wang; Na Li; Dajun Yang; Yifan Zhai

doi:10.1016/j.tranon.2021.101244

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Transl Oncol. 2022 Jan;15(1):101244. doi: 10.1016/j.tranon.2021.101244. Epub 2021 Oct 25.

Authors

Douglas D Fang¹, Hengrui Zhu¹, Qiuqiong Tang¹, Guangfeng Wang¹, Ping Min¹, Qixin Wang¹, Na Li¹, Dajun Yang², Yifan Zhai³

Affiliations

¹ Ascentage Pharma (Suzhou) Co, Ltd, 218 Xinghu Street, Suzhou, Jiangsu Province, China.
² Ascentage Pharma (Suzhou) Co, Ltd, 218 Xinghu Street, Suzhou, Jiangsu Province, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
³ Ascentage Pharma (Suzhou) Co, Ltd, 218 Xinghu Street, Suzhou, Jiangsu Province, China. Electronic address: yzhai@ascentage.com.

Abstract

Introduction: FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes.

Materials and methods: Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo. A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination.

Results: HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4-11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells.

Conclusions: FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.

Keywords: APG-2575; Acute myeloid leukemia; BCL-2; FLT3-ITD; HQP1351.