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Mechanisms of resistance

Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia

Leukemia volume 29, pages 2382–2389 (2015)Cite this article

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Abstract

In acute myeloid leukemia (AML), about 25–30% of patients harbor a constitutively active receptor tyrosine kinase (RTK) FLT3 encoded by a FLT3 allele harboring internal tandem duplication (FLT3-ITD) mutation. The presence of FLT3-ITD correlates with poor prognosis in AML and it makes FLT3 an attractive therapeutic target in AML. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts resistant to FLT3 inhibitors detected in blood or bone marrow. In this study, we investigated whether the RTK Axl is responsible for resistance of FLT3-ITD+ AML cells to PKC412 and AC220, FLT3 inhibitors currently under clinical trials for FLT3-ITD+ AML patients. Upon treatment with PKC412 or AC220, phosphorylation of Axl was significantly enhanced in the FLT3-ITD+ MV4-11 AML cell line and in primary blasts from a FLT3-ITD+ AML patient. Consistently, a PKC412-resistant AML cell line and PKC412-resistant primary blasts from FLT3-ITD+ AML patients had significantly higher levels of constitutively phosphorylated Axl and total Axl when compared with a PKC412-sensitive AML cell line and PKC412-sensitive primary blasts from FLT3-ITD+ AML patients. We also found that resistance of AML cells against the FLT3 inhibitor PKC412 and AC220 was substantially diminished by the inhibition of Axl via a small-molecule inhibitor TP-0903, a soluble receptor Axl fusion protein Axl-Fc or knockdown of Axl gene expression by shRNA. Collectively, our study suggests that Axl is required for resistance of FLT3-ITD+ AML cells against the FLT3 inhibitor PKC412 and AC220, and that inhibition of Axl activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD+ AML.

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Acknowledgements

We thank the OSUCCC Leukemia Tissue Bank Shared Resource for providing AML patient samples. We also acknowledge Tolero Pharmaceuticals for providing the Axl inhibitor TP-0903. This work was supported by National Cancer Institute grants (CA16058 and CA89341 to MAC) and P50 SPORE grant (CA140158 to GM and MAC). I-KP and BM-B were supported by NCI T32 training grants (CA933835).

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Authors and Affiliations

  1. Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA

    I-K Park, B Mundy-Bosse, S P Whitman, W Blum, G Marcucci & M A Caligiuri

  2. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Zhang

  3. Tolero Pharmaceuticals, Inc., Lehi, UT, USA

    S L Warner & D J Bearss

  4. Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA

    W Blum, G Marcucci & M A Caligiuri

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Correspondence to M A Caligiuri.

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SLW and DJB are employees of and shareholders in Tolero Pharmaceuticals, Inc. The remaining authors declare no conflict of interest.

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Park, IK., Mundy-Bosse, B., Whitman, S. et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia 29, 2382–2389 (2015). https://doi.org/10.1038/leu.2015.147

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