The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

Yang Qiu; Ying Li; Meng Chai; Huiming Hua; Rui Wang; Samuel Waxman; Yongkui Jing

doi:10.1038/s41420-023-01317-0

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

Cell Death Discov. 2023 Feb 4;9(1):44. doi: 10.1038/s41420-023-01317-0.

Authors

Yang Qiu¹, Ying Li¹, Meng Chai¹, Huiming Hua², Rui Wang³, Samuel Waxman³, Yongkui Jing⁴

Affiliations

¹ Liaoning Key Lab of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
³ The Division of Hematology/Oncology, Department of Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁴ Liaoning Key Lab of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China. Jingyk@syphu.edu.cn.

Abstract

Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.