Drugs targeting Gene Fusions

Question

[Ron]

Hello ,

I wanted to know if gene fusions from RNAseq data can be said druggable based on one of the genes being druggable or it has to be druggable as a fusion ? I would like to look into the drugs that bind to the genes from fusions,so which one would be the right way to look into the data.

This resource has drugs interacting with gene fusions themselves. http://depo-dinglab.ddns.net/

If a fusion has to be druggable, are there more such resources of the known interactions? For drug- gene interactions I found this really good resource . http://dgidb.org/getting_started

Thanks

Ron

Answer 1

[Matthias Zepper]

Hello Ron,

I think this very much depends on your definition of druggable and the mode of action of the drug in question, so I would be careful to generalize here.

Consider for example MLL-fusions, a well known oncogene in hematopoietic malignancies (nicely reviewed e.g. by Robert Slany PMID 26923329). There are several known fusion partners and 70 something breakpoints in the gene, so some fusions will retain more or less of the MLL protein than others. Just because a drug will target a specific MLL fusion doesn't mean it will target all.

Another example that comes to my mind is resistance to Imatinib treatment due to activating mutations in the tyrosine kinase c-Kit (see e.g Growney et al. PMID 15790786), so even in the case of just a single gene instead of a fusion it isn't guaranteed that a drug that nominally targets that gene will work for an individual patient.

Best Matthias

[Ron]

So it is best to look at drug interactions with the gene fusion themselves ? I mean , A drug that would work for lets say ERBB2--CDK12 fusion would not work for ERBB2--PGAP3 fusion ? Or it can be considered druggable , based on how the gene fusion product is ?

On the contrary, it seems NTRK fusions and FGFR fusions which got recently approved drugs target all the fusions involving these genes?