Signalling Networks in Cancer
Driver mutations: a roadmap for the identification of protein kinases involved in cancer. Cancer genomic studies have illuminated the complex nature of cancer and made it apparent that there are numerous and distinct mutations present in every tumor. This information can be used to identify novel common and convergent molecular mechanisms employed by cancer cells to promote the stepwise process of tumor formation. Cancer genomic sequencing studies can successfully identify pathways that are inactivated or constitutively activated, and experimental analysis of signalling proteins with frequent mutations in cancer, such as B-RAF and PIK3CA, demonstrates they play a casual role in tumorigenesis. Going forward new approaches must be developed to identify proteins that are mutated at a lower frequency yet are still crucial for tumorigenesis and thus harbour somatic driver mutations. To this end we have used a bioinformatics approach to identify novel or understudied kinases where all or a vast majority of somatic and germline mutations are predicted to be driver mutations and therefore likely alter the function of a kinase so that it is essential for tumor evolution. A major focus of our group is to investigate if the reported cancer mutations in top candidate kinases play a role in cell transformation and tumorigenesis, with the potential of identifying new target pathways for therapeutic intervention.
We will also focus on studying the PKC family of kinases, which have been intensely investigated for over 25 years in the context of cancer. Historically, this arises from the discovery of PKC as the receptor for the tumor-promoting phorbol esters, which suggested that activation of PKC by phorbol esters promoted tumorigenesis induced by carcinogens. However, this interpretation is now open to question, since long-term treatment with phorbol esters is known to initiate degradation of PKC, thus down-regulating its activity. The second aim of our research will focus on determining if PKC mutations inhibit or activate PKC isozymes and how this complements other mutations acquired in a given tumor, such as activating K-Ras mutations.