Mutations, good and bad, are the natural order of species

"The development, survival, and reproduction of an organism depend on the genetic information that is carried in its genome, yet the transmission of genetic information is not perfectly accurate: new mutations occur at each generation. These mutations are the primary cause of the genetic diversity on which natural selection can operate, and hence are the sine qua non of evolution. A better knowledge of mutation processes is crucial for investigating the causes of genetic diseases or cancer and for understanding evolutionary processes."

Laurent Duret, PLoS Biology

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

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