Pharma Strategy Blog

So wrote Duret in a brief article I was reading earlier today in my Google Reader.  While mutations are essential for increased diversity in a species, not all mutations, however, are necessarily a good thing. 

We have seen the negative impact in diseases such as Philadelphia positive (Ph+) acute leukemia and advanced chronic myeloid leukemia, where worsening of the disease occurs as well as increased resistance to drug therapy with available tyrosine kinase inhibitors such as imatinib, dasatinib and nilotinib.  Mutations present in the kinase domain of the Bcr-Abl gene of
these patients suffering from CML or Ph+ ALL account for the biological
resistance of these patients towards drug treatment, in that the
mutations lead to resistance of the Bcr-Abl tyrosine kinase towards
inhibition.  Indeed, one of the mutations, T315l, cannot be inhibited by any of the targeted drugs currently on the market.

These findings are extremely valuable in finding new compounds or combinations of agents, which are able to overcome resistance towards treatment with the tyrosine kinase inhibitors.  In addition, knowledge of such mutations is also very useful in the diagnosis of Ph+
leukemias, in that it allows the detection of drug-resistant clones
before the clinical relapse of the patient.

The good news though, is newer, more targeted therapies are being currently being developed to address this, although it is far too early to tell if they will be successful or not.  One of the more promising ones is AP24534, from Ariad, which is currently being investigated in phase I.

Laurent Duret (2009). Mutation Patterns in the Human Genome: More Variable Than Expected PLoS Biology, 7 (2) DOI: 10.1371/journal.pbio.1000028