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Activity of TP‐0903 in FLT3 inhibitor resistant AML models
Author(s) -
Jeon Jae Yoon,
Garrison Dominique,
Thomas Megan Zavorka,
Buelow Daelynn,
Whatcott Clifford,
Warner Steve,
Byrd John,
Bhatnagar Bhavana,
Baker Sharyn D
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.675.4
Subject(s) - cancer research , myeloid leukemia , fms like tyrosine kinase 3 , tyrosine kinase , tyrosine kinase inhibitor , pharmacology , chemistry , biology , medicine , signal transduction , mutation , microbiology and biotechnology , cancer , biochemistry , gene
Background The development of tyrosine kinase inhibitors (TKIs) for the treatment of acute myeloid leukemia (AML) with FLT3 internal tandem duplication mutations ( FLT3 ‐ITD+) has been challenging due to intrinsic and acquired drug resistance. Important resistance mechanisms that have been described include: 1) the emergence of secondary FLT3 tyrosine kinase domain (TKD) mutations; 2) compensatory signaling pathways (intrinsic to the leukemia cell or due to tumor‐microenvironment interactions), such as Gas6/Axl upregulation; and 3) the co‐occurrence of somatic mutations with FLT3 ‐ITD, such as IDH 1/2, NRAS and MLL ‐PTD. TP‐0903, is a new TKI in development as an Axl inhibitor. Previously, we demonstrated that TP‐0903 is a potent inhibitor of FLT3‐ITD and drug resistant FLT3 TKD mutations in preclinical in vitro and in vivo models (Jeon JY et al. ASH 2017). Here, we present the activity of TP‐0903 in additional TKI‐resistant models of FLT3‐ITD+ AML in comparison to other FLT3 TKIs. Methods FLT3 ‐ITD+ MOLM13 cells were seeded in direct co‐culture with or without HS5‐GFP bone marrow stromal cells (MSCs) for 24h followed by 72h treatment with TP‐0903 or 5 other clinical candidate FLT3 TKIs; cell viability of co‐cultured MOLM13 cells was measured via MTT assay. Soluble Gas6 and Axl were measured in co‐cultured media over 24–72h by ELISA. Ex vivo activity of TKIs on the viability of murine primary leukemia cells with FLT3 ‐ITD +/− / IDH 2‐R140Q +/− or FLT3 ‐ITD +/− / MLL ‐PTD co‐occurring mutations was assessed after 72h TKI treatment using a CellTiter Glo assay. Results The effect of TP‐0903 and other FLT3 TKIs on the inhibition of viability of MOLM13 cells cultured with or without MSCs is shown in Table 1. While co‐culture induced a minimal 1.7‐fold shift in the TP‐0903 IC50 value, the other FLT3 TKIs were more resistance in co‐culture, with gilteritinib and sorafenib showing the greatest change in IC50 values (4.9‐ and 5.0‐fold). Soluble Axl and Gas6 levels increased over 24–72h in co‐cultured media with the highest concentrations achieved of 1455 ± 322 pg/mL and 5098 ± 974 pg/mL, respectively. In primary FLT3 ‐ITD +/− / IDH2 ‐R140Q +/− leukemia cells, TP‐0903 was 8‐ to 10‐fold more potent than gilteritinib and crenolanib, whereas midostaurin, quizartinib and sorafenib did not show activity in these cells (Table 1). TP‐0903 was also 5‐fold more potent than gilteritinib in primary FLT3 ‐ITD +/− / MLL ‐PTD leukemia cells. Ongoing studies are evaluating the effect of soluble Gas6 on TKI sensitivity in AML cells, as well as the in vivo activity of TP‐0903 in FLT3 ‐ITD +/− / IDH 2‐R140Q +/− or FLT3 ‐ITD +/− / MLL ‐PTD spontaneous mouse models. Conclusions TP‐0903 retains activity in preclinical models of intrinsic/acquired FLT3 TKI resistance with therapeutic potential to overcome drug resistant FLT3 ‐ITD+ AML. Support or Funding Information This work is supported by Eli Lilly fellowship and NIH grant 5R01CA138744‐09 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .