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
Affiliations
Daniel J.L. Coleman
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; Corresponding author
Peter Keane
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Paulynn S. Chin
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Luke Ames
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Sophie Kellaway
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Helen Blair
Wolfson Childhood Cancer Research Centre, University of Newcastle, Newcastle upon Tyne, UK
Naeem Khan
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
James Griffin
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Elizabeth Holmes
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Alexander Maytum
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Sandeep Potluri
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Lara Strate
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Kinga Koscielniak
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Manoj Raghavan
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
John Bushweller
School of Medicine, University of Virginia, Charlottesville, VA, USA
Olaf Heidenreich
Wolfson Childhood Cancer Research Centre, University of Newcastle, Newcastle upon Tyne, UK; Princess Máxima Centrum of Pediatric Oncology, Utrecht, the Netherlands
Terry Rabbitts
Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
Peter N. Cockerill
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
Constanze Bonifer
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; Corresponding author
Summary: 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.
