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Jan 15, 2009 (Vol. 29, No. 2)

Finessing PI3 Kinase Assay Development

DxS Works to Overcome the Psuedogene Problem

  • The EGFR cell-signaling pathway plays a central role in processes such as cell growth, proliferation, survival, and differentiation. Understanding the biological role of this pathway and its effect in various cancer types has led to the development of several therapeutic approaches that target this pathway, including monoclonal antibodies that inhibit the EGF-receptor and block the activation of the signaling cascade, and small molecule inhibitors. 

    When these drugs were put through clinical trials, however, it was discovered that a group of the population tested did not gain any benefit from the therapy. Further investigation into the mutation status of those people who showed no improvement with the drug revealed that mutations in genes involved in the EGFR cell signaling pathway, such as K-RAS, B-RAF, and PI3 kinase, affected the response to therapy. This has led to personalized medicine taking a more central role in selecting cancer therapies for an individual.

  • PI3 Kinase as a Target

    Phosphatidylinositol 3-kinases (PI3K) are heterodimeric lipid kinases involved in cell signaling. There are three classes of PI3-kinases, the PIK3CA gene is found in class I. Class I PI3 kinase is made up of two specific parts, an 85kDa subunit, p85, which is an adaptor molecule that has no catalytic function but attaches the unit to the receptor, and a 110kDa subunit, p110, which triggers the phosphorylation events in the PI3K-AKT pathway. 

    The active part of PI3K (p110) is encoded for by the gene PIK3CA. Activity of PI3 kinase was first reported to be associated with viral oncogenes in 1991 and, more recently, mutations in the PIK3CA gene have been identified in human cancers.

    It has been suggested that the presence of PIK3CA mutations in a tumor can act as a prognostic factor and may predict the response to treatment. This makes the PIK3CA gene attractive as a potential target for anticancer therapies. 

    There are three mutation hotspots in the PIK3CA gene: E542K and E545K in exon 9, and H1047R in exon 20, these mutations represent >80% of all PIK3CA mutations described. The frequency of PIK3CA mutations in colon, breast, lung, and melanoma cancers have been estimated at 10.2%, 38.7%, 1.9%, and 2.9%, respectively. 

    DxS has developed a real-time PCR assay using its technologies to detect mutations in the three hotspots of the PIK3CA gene and also one rare mutation, E545D, also found in exon 9. DxS has previously developed mutation detection kits using the same technologies for other genes in the EGFR pathway such as EGFR, K-RAS, and B-RAF. 

    The DxS PI3K Mutation Test Kit follows the same format as other kits in the DxS product portfolio using Amplification Refractory Mutation System (ARMS®; AstraZeneca) and Scorpions® (DxS) technologies.


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