Oncotarget

Research Papers:

Modelling ponatinib resistance in tyrosine kinase inhibitor-naïve and dasatinib resistant BCR-ABL1+ cell lines

Liu Lu, Chung Hoow Kok, Verity Ann Saunders, Jueqiong Wang, Jennifer Anne McLean, Timothy Peter Hughes and Deborah Lee White _

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Oncotarget. 2018; 9:34735-34747. https://doi.org/10.18632/oncotarget.26187

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Abstract

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

Correspondence to:

Deborah Lee White, email: Deborah.white@sahmri.com

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

ABSTRACT

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.


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