Modelling ponatinib resistance in tyrosine kinase inhibitor-naïve and dasatinib resistant BCR-ABL1+ cell lines
Metrics: PDF 1465 views | HTML 3246 views | ?
Liu Lu1,2, Chung Hoow Kok1,2, Verity Ann Saunders1, Jueqiong Wang3, Jennifer Anne McLean1, Timothy Peter Hughes1,2,6 and Deborah Lee White1,2,4,5
1South Australian Health and Medical Research Institute (SAHMRI), Cancer Theme, Adelaide, SA, Australia
2School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
3Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
4Discipline of Paediatrics, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
5School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, SA, Australia
6Department of Haematology, SA Pathology, Adelaide, SA, Australia
Deborah Lee White, email: [email protected]
Keywords: chronic myeloid leukaemia; ponatinib resistance; Bcr-Abl+ cell lines; compound mutation; Axl
Received: June 30, 2018 Accepted: September 15, 2018 Published: October 05, 2018
TKI resistance remains a major impediment to successful treatment of CML. In this study, we investigated the emerging modes of ponatinib resistance in TKI-naïve and dasatinib resistant BCR-ABL1+ cell lines. To investigate potential resistance mechanisms, ponatinib resistance was generated in BCR-ABL1+ cell-lines by long-term exposure to increasing concentrations of ponatinib. Two cell lines with prior dasatinib resistance demonstrated BCR-ABL1 kinase domain (KD) mutation(s) upon exposure to ponatinib. In one of these cell lines the T315I mutation had emerged during dasatinib exposure. When further cultured with ponatinib, the T315I mutation level and BCR-ABL1 mRNA expression level were increased. In the other cell line, compound mutations G250E/E255K developed with ponatinib exposure. In contrast, the ponatinib resistant cell lines that had no prior exposure to other TKIs (TKI-naïve) did not develop BCR-ABL1 KD mutations. Rather, both of these cell lines demonstrated Bcr-Abl-independent resistance via Axl overexpression. Axl, a receptor tyrosine kinase, has previously been associated with imatinib and nilotinib resistance. Ponatinib sensitivity was restored following Axl inhibition or shRNA-mediated-knockdown of Axl, suggesting that Axl was the primary driver of resistance and a potential target for therapy in this setting.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.