The PIK3CA gene as a mutated target for cancer therapy

Abstract

The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Recently, our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on PIK3CA inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.

Figure 1

A representation of the domains of the PI3K subunits p110α and p85α. The p110α catalytic subunit has 5 domains including adaptor-binding domain (ABD), the Ras-binding domain (RBD), a calcium binding domain (C2), a helical domain and a kinase domain. The p85α regulatory subunit contains 5 domains as well, which include a Src homology 3 domain (SH3), a GTPase activating protein domain (GAP), an N-terminal Src homology 2 domain (nSH2), an inter- Src homology 2 domain (iSH2), and a C-terminal Src homology 2 domain (cSH2). The exon 9 hotspot mutations, E542K and E545K, occur in the helical domain of the catalytic subunit p110α, and the charge reversal caused by these mutations inhibits electrostatic interactions between those amino acids on the p110α helical domain and R340 and K379 on the nSH2 domain of p85α. The exon 20 hotspot mutation, H1047R, is in the kinase domain of p110α, and this mutation has been proposed to form a hydrogen bond with L956 of p110α, which in turn leads to catalytic activity of p110α.