Insulin-Like Growth Factor 1 Receptor (Igf1r) Inhibitor Bms754807 Is Active Against Flt3-Itd Mutated Acute Myelogenous Leukemia And Activity Is P53 Dependent

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The Internal tandem mutation (ITD) in the FLT3 gene is associated with shorter remission duration, overall survival and relapse free survival in patients with normal karyotype acute myelogenous leukemia (AML). FLT3-ITD inhibitors are in clinical development but single agent clinical activity is of limited duration with activation of parallel signaling pathways potentially contributing to most relapses thus highlighting the need for new agents. Because common signaling pathways are activated downstream of FLT3 and IGF1R, we investigated the preclinical activity of IGF1R antagonist BMS754807 against AML cells with FLT3-ITD mutations. Results: BMS 754807 induced apoptosis (Annexin V binding by flow cytometry) in MOLM13 cells (AML cell line with FLT3-ITD mutation and wild type p53) at 48 hrs at submicromolar concentrations, while OCI AML3 cells (p53 and FLT3 wild type) were resistant. Similarly, murine BAF3 cells expressing human FLT3-ITD underwent prompt apoptosis with BMS 754807 while the same cells with human wt-FLT3 were resistant to BMS 754807(IC50s 2.5 μmol vs >10 μmol). Western blot analysis confirmed reduction in FLT3, Akt, ERK, S6 ribosomal protein and GSK3 beta phosphorylation and increase in p53 levels in MOLM13 cells. Interestingly, apoptosis induction was not associated with caspase activation. Moreover, apoptosis induction by BMS 754807 appeared to be p53 dependent as MOLM13 cells with stable expression of short hairpin RNA (sh-RNA) targeting p53 (p53-shRNA) were resistant, while MOLM13 cells expressing scramble sh-RNA underwent apoptosis comparable to parental MOLM13 cells. Surface expression of IGF1R was comparable among parental and p53-shRNA MOLM13 cells. Apoptosis induction by BMS 754807 in p53-WT and FLT3-ITD cells was associated with phosphorylation of p53 at serine 15. Conclusion: BMS 754807 has selective activity against AML cells with FLT3-ITD mutation and this activity is p53 dependent and associated with phosphorylation of p53 at serine 15. Results suggest that IGF1R inhibition has therapeutic potential as novel targeted therapy for AML with FLT3-ITD mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3871. doi:1538-7445.AM2012-3871