EHA 2016
Modelling ponatinib resistance in BCR-ABL1 cell lines
Dr Liu Lu - South Australian Health and Medical Research Institute, Adelaide, Australia
My research is about generating ponatinib resistant CML cell line models. So because ponatinib is now used as a second line therapy in CML, chronic myeloid leukaemia, but we don’t really know what mechanism causes ponatinib resistance and that’s my research I mean to do to investigate the resistance mechanisms but in cell line models.
How have you been modelling cell lines compared to human tissues?
The cell line is derived from human blast crisis cells and at least it’s in certain types of similar. It’s not really the same as in humans but in previous publications what we see from the cell line, the resistance mechanisms, most of them can apply in humans so it’s quite applicable.
Are there any regions of genes that you’ve been working with especially?
Because BCR-ABL is a gene in CML that causes this disease so obviously we will monitor the BCR-ABL1 gene very regularly in my resistant line. The other thing is we also monitor any gene that gets modified in my resistant line just to check what’s the reason to cause resistance. There’s one, it’s called AXL, it’s a receptor tyrosine kinase and it was found to cause AML, CML and multiple other cancers. What we find here in CML is this gene got expressed in the ponatinib resistant cell lines and it may be applied in humans as well.
When it comes to the results of this trial, figuring out the resistance, can you tell us more about that?
So I have generated four ponatinib resistant cell lines, two of them have been exposed to the other TKIs before so it has been exposed to dasatinib before ponatinib because ponatinib is the second line so when a patient goes to ponatinib most of them have been exposed to the other TKIs before. In these two cell lines BCR-ABL dependence resistance mechanisms are the main reason to cause resistance and this includes BCR-ABL overexpression or mutations, compound mutations in BCR-ABL. I have another two cell lines that have never been exposed to other TKIs before ponatinib and in these two cell lines, like I said before, the AXL overexpression is the reason to cause resistance in these two models.
Do you think these might be the leading drivers in resistance or is there more yet to find?
I’m quite confident with my results that in the TKI naïve setting BCR-ABL independent resistance including AXL overexpression or other signalling overexpressed or downregulated is the reason to cause resistance to ponatinib. In the setting of the cell line or even maybe in patients that have been exposed to the other TKIs before ponatinib, that compound mutation may actually lead to the resistance if the resistance ever happens.
Do you know if the regions, the AXL, the BCR-ABL have been implicated in other resistances beyond these TKIs?
Compound mutations have been observed more frequently in the CML patients especially when they have sequential TKI treatment including imatinib, erlotinib or dasatinib and then ponatinib. BCR-ABL independent mechanism is less but has been observed before as well so it’s still a possible reason to cause resistance. If you’re talking about different diseases other than CML like maybe ALL because ponatinib and the other TKIs also use in pH positive ALL so a similar mechanism will also cause resistance in ALL.
