Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1

Daniel J L Coleman*, Peter Keane, Paulynn S Chin, Luke Ames, Sophie Kellaway, Helen Blair, Naeem Khan, James Griffin, Elizabeth Holmes, Alexander Maytum, Sandeep Potluri, Lara Strate, Kinga Koscielniak, Manoj Raghavan, John Bushweller, Olaf Heidenreich, Terry Rabbitts, Peter N Cockerill, Constanze Bonifer*

*Corresponding author for this work

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Abstract

AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.

Original languageEnglish
Article number109576
JournaliScience
Volume27
Issue number4
Early online date26 Mar 2024
DOIs
Publication statusPublished - 19 Apr 2024

Bibliographical note

© 2024 The Author(s).

Acknowledgments
This work was funded by grants from Blood Cancer UK (15001) and the Medical Research Council (MRC) to C.B., P.N.C. and O.T.H. (MR/S021469/1); grants from Leukemia UK (2021/JGF/001), from the National Institutes of Health to J.B (R01 CA234478), the Royal Society (RGS\R2\222022) and Wellcome and the University of Birmingham to D.J.L.C. D.L.C. is a John Goldman Fellow from Leukemia UK. Work on RAS inhibitors in T.H.R.’s lab is funded by Cancer Research UK (ICR Core), Blood Cancer UK (19013), Kay Kendall Leukaemia Fund (KKL 1326), CRUK/NCI grant CGCATF-2021/100011).
We thank Genomics Birmingham for next generation, expert sequencing provision, Samantha Jepsen Gibson for expert assistance with the mouse work, and Guillaume Desanti and Ferdus Sheik of the University of Birmingham Flow Cytometry facility for their support of cell sorting experiments.

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