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Translational Therapeutics

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells

British Journal of Cancer volume 125, pages 966–974 (2021)Cite this article

Subjects

Abstract

Background

Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) are among the most prevalent oncogenic mutations in acute myeloid leukaemia. Inhibitors selectively targeting FLT3 kinase have shown promising clinical activity; their success in the clinic, however, has been limited due to the emergence of acquired resistance.

Methods

CCT245718 was identified and characterised as a dual Aurora A/FLT3 inhibitor through cell-based and biochemical assays. The ability of CCT245718 to overcome TKD-mediated resistance was evaluated in a cell line-based model of drug resistance to FLT3 inhibitors.

Results

CCT245718 exhibits potent antiproliferative activity towards FLT3-ITD + AML cell lines and strongly binds to FLT3-ITD and TKD (D835Y) mutants in vitro. Activities of both FLT3-ITD and Aurora A are also inhibited in cells. Inhibition of FLT3 results in reduced phosphorylation of STAT5, downregulation of survivin and induction of apoptotic cell death. Moreover, CCT245718 overcomes TKD-mediated resistance in a MOLM-13-derived cell line containing FLT3 with both ITD and D835Y mutations. It also inhibits FLT3 signalling in both parental and resistant cell lines compared to FLT3-specific inhibitor MLN518, which is only active in the parental cell line.

Conclusions

Our results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance.

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Fig. 1: Small molecule inhibitors of FLT3 and Aurora kinases.
Fig. 2: Inhibition of Aurora A and FLT3 in AML cell lines.
Fig. 3: CCT245718 directly binds to and inhibits FLT3 activation.
Fig. 4: Effect of CCT245718 on cell cycle profile in THP1, MV-4-11 and MOLM-13 cells.
Fig. 5: CCT245718 induces apoptosis in AML cell lines.
Fig. 6: CCT245718 overcomes TKD-mediated resistance.

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Acknowledgements

We thank Dr. Safee Ullah Chaudhary and Dr. Ahmad Jawad Afzal for carefully reading the manuscript and providing useful insights.

Funding

This study was supported by generous grants from Lahore University of Management Sciences to Amir Faisal (Faculty Initiative Fund-253 and Startup Grant STG-064).

Author information

Author notes

  1. Spiros Linardopoulos

    Present address: AstraZeneca, Cambridge, UK

Authors and Affiliations

  1. Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan

    Muhammad Usama Tariq, Muhammad Furqan, Hira Parveen, Rahim Ullah & Amir Faisal

  2. Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan

    Muhammad Muddassar

  3. Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan

    Rahman Shah Zaib Saleem

  4. Cancer Research UK, Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK

    Vassilios Bavetsias & Spiros Linardopoulos

  5. Breast Cancer Now, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK

    Spiros Linardopoulos

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Contributions

AF, VB and SL conceived and designed the study with MUT providing additional input. AF, MUT, MF, HP, RU and MM performed all the experiments. MUT, HP and AF wrote the manuscript. RSZS, VB and SL helped in writing and reviewing the manuscript. MF helped in the revision of the manuscript. AF supervised the whole study. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Amir Faisal.

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Peripheral blood mononuclear cells (PBMCs) were isolated from blood taken from consenting healthy volunteers after approval from Institutional Review Board.

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Some of the authors are current (VB) or former (SL and AF) employees of The Institute of Cancer Research which operates a rewards to inventors scheme applicable to all current and former employees. For all the other authors, there is no financial or commercial conflict of interest.

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Tariq, M.U., Furqan, M., Parveen, H. et al. CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells. Br J Cancer 125, 966–974 (2021). https://doi.org/10.1038/s41416-021-01527-2

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