Abstract 4217: Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia

HQP1351 is a novel, orally bioavailable multi-kinase inhibitor targeting BCR-ABL, KIT, and FLT3. Currently, HQP1351 is in phase II clinical trials in relapsed and refractory chronic myeloid leukemia (CML) patients by targeting BCR-ABL. Besides, HQP1351 inhibits both wild-type and mutant FLT3 in kinase binding assay. APG-115 is another clinical stage, small molecule MDM2 antagonist. In the present study, we explored the antitumor effect of the combination of HQP1351 and APG-115, and the molecular mechanism in FLT3-ITD and TP53 wild-type acute myeloid leukemia (AML) in the preclinical setting. First, the effect of HQP1351 as single agent on cell viability in FLT3-ITD mutant and TP53 wild-type human AML cell lines, including MV-4-11 and MOLM-13. Second, antitumor activity of the combination was investigated in systemic and subcutaneous xenograft models in NOD/SCID mice derived from these cells. The results showed that HQP1351 alone exhibited potent antiproliferative activity in both cell lines in vitro, with nanomolar IC50 values. The activity was enhanced in the combination treatment with APG-115. In vivo, HQP1351 single agent demonstrated significant antitumor activity evidenced by a markedly reduction of tumor burden (i.e., CD45+ human tumor cells) in systemic MOLM-13 xenograft model. Treatment with HQP1351 at 3, 10 and 30 mg/kg significantly prolonged mice survival with median survival of 20.5 days, 26.0 days and 35 days, respectively, compared with 18 days in the control group. In subcutaneous MV-4-11 xenograft model, treatment with HQP1351 or APG-115 single agents achieved T/C values of 28.6% and 59.6%, respectively. The combination achieved synergistic antitumor activity with a T/C value of 13.4%. The benefit of the combination was also demonstrated in systemic MOLM-13 xenograft model. Mechanistically, the combined treatment synergistically downregulated p-FLT3, p-ERK, p-STAT5 and anti-apoptotic protein MCL-1, and thus enhanced antitumor effect. Taken together, our data provide scientific rationale for clinical development of the combination of HQP1351 and APG-115 in FLT3-ITD mutant and TP53 wild-type AML patients. Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Jiaxing Gu, Yanhui Kong, Tao Rong, Guangfeng Wang, Dajun Yang, Yifan Zhai. Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia [abstract]. In: Proceedings of th