Frontiers in Oncology (Jan 2022)
Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia
- Mawar Karsa,
- Mawar Karsa,
- Emma Ronca,
- Angelika Bongers,
- Anna Mariana,
- Anna Mariana,
- Ernest Moles,
- Ernest Moles,
- Ernest Moles,
- Timothy W. Failes,
- Timothy W. Failes,
- Greg M. Arndt,
- Greg M. Arndt,
- Greg M. Arndt,
- Laurence C. Cheung,
- Laurence C. Cheung,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Rishi S. Kotecha,
- Maria Kavallaris,
- Maria Kavallaris,
- Maria Kavallaris,
- Michelle Haber,
- Michelle Haber,
- Murray D. Norris,
- Murray D. Norris,
- Murray D. Norris,
- Michelle J. Henderson,
- Michelle J. Henderson,
- Lin Xiao,
- Lin Xiao,
- Klaartje Somers,
- Klaartje Somers
Affiliations
- Mawar Karsa
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Mawar Karsa
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Emma Ronca
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Angelika Bongers
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Anna Mariana
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Anna Mariana
- Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Ernest Moles
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Ernest Moles
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Ernest Moles
- Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for Nanomedicine, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Timothy W. Failes
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Timothy W. Failes
- Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Greg M. Arndt
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Greg M. Arndt
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Greg M. Arndt
- Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia
- Laurence C. Cheung
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia
- Rishi S. Kotecha
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Rishi S. Kotecha
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA, Australia
- Rishi S. Kotecha
- Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia
- Maria Kavallaris
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Maria Kavallaris
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Maria Kavallaris
- Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for Nanomedicine, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Michelle Haber
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Michelle Haber
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Murray D. Norris
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Murray D. Norris
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Murray D. Norris
- University of New South Wales (UNSW) Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Michelle J. Henderson
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Michelle J. Henderson
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Lin Xiao
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Lin Xiao
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Klaartje Somers
- Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- Klaartje Somers
- School of Women’s and Children’s Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia
- DOI
- https://doi.org/10.3389/fonc.2021.779859
- Journal volume & issue
-
Vol. 11
Abstract
Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.
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