Combination of a mitogen-activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion-based residual disease and prevents re-expansion of FLT3-ITD acute myeloid leukaemia
| Autor: | Joanna Zabkiewicz, Nader Omidvar, Alan Kenneth Burnett, Carol Guy, Steve Knapper, Michelle Lazenby, Robert Kerrin Hills, Gareth Edwards, Lihui Zhuang, Ceri Bygrave, Caroline Alvares |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Bridged-Ring Compounds Male Neoplasm Residual Adolescent medicine.drug_class Models Biological Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Stroma hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Cell Adhesion Humans Protein kinase A Child Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Aged business.industry Infant Newborn Mitogen-Activated Protein Kinase Inhibitor Infant Hematology Middle Aged Minimal residual disease Transplantation Leukemia Myeloid Acute Pacritinib Pyrimidines fms-Like Tyrosine Kinase 3 030220 oncology & carcinogenesis Child Preschool Cancer research Female Stem cell business 030215 immunology |
| Zdroj: | British journal of haematologyReferences. 191(2) |
| ISSN: | 1365-2141 0007-1048 |
| Popis: | Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first‐generation FMS‐like tyrosine kinase 3 (FLT3) inhibitors in pre‐ and post‐transplant regimes and as maintenance in FLT3 ‐mutated AML. Pre‐clinical progress is hampered by the lack of suitable modelling of residual disease and post‐therapy relapse. In the present study, we investigated the nature of pro‐survival signalling in primary residual tyrosine kinase inhibitor (TKI)‐treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia‐human stroma model to mimic the cell–cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma‐driven leukaemic signalling was determined, and a synergistic combination with a mitogen‐activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma‐mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment‐related toxicity. |
| Databáze: | OpenAIRE |
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