Abstract 4489: Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells

Abstract Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors developed only result in transient disease remission with disease relapse and resistance. Agents overcoming FLT3-ITD inhibitor resistance need to be developed. Sorafenib is one of FLT3-ITD inhibitors used in clinic. Using FLT3-ITD AML MOLM-13 cell line, we established a sorafenib resistant subclone MOLM-13/Sor, explored the resistance mechanism and revealed the overactivated mTOR signaling. MNK as one of the alternative mTOR signaling pathways is activated. MNK inhibitor eFT508 could overcome sorafenib resistance. Previously we developed a dual pyrido[3,2-d]pyrimidine MNK/PIM inhibitor 21o. Through optimization of 21o we obtained two new compounds H104 (IC50 values: MNK1 19 nM; MNK2 8 nM; FLT3-ITD 46 nM; PIM1 1388 nM) and H118 (IC50 values: MNK1 35 nM; MNK2 21 nM; FLT3-ITD 25 nM; PIM1 518 nM) with selective inhibition of MNK and FLT3 and losing PIM inhibition ability. H104 and H118 show better antiproliferative efficacy in FLT3-ITD MOLM-13 cells (GI50: 1.07±0.04 μM and 0.99±0.08 μM) than non-FLT3-ITD HL-60 cells (GI50: 7.04±0.15 μM and 4.78±0.31 μM). More intriguingly H104 and H118 exhibit superior antiproliferative effects in sorafenib resistant MOLM-13/Sor cells (GI50: 0.44±0.05 μM and 0.24±0.06 μM). H104 and H118 decreased the levels of p-eIF4E, c-myc and Mcl-1, the downstream substrates of FLT3-ITD and MNK. Our data indicate that the activated MNK is one mechanism of FLT3-ITD resistance and the dual MNK/FLT3 inhibitors have advantage for FLT3-ITD AML treatment. Citation Format: Linxiang Zhao, Shuwei Zuo, Kun Xing, Xiaoshuang Yue, Huimin Zhang, Jingyi Zhang, Samuel Waxman, Yongkui Jing. Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4489.