Inhibiting the RAS-PI3K pathway in cancer therapy.

ABSTRACT

The PI3K pathway is over-activated in the majority of human cancers. This may occur through oncogenic activation of upstream RAS isoforms and tyrosine kinase receptors, or by mutational activation of components of the PI3K pathway themselves. Stimulation of the PI3K pathway enhances growth, survival, and metabolism of cancer cells. Migration, invasion, and angiogenesis are also supported by PI3K signaling. Thus, the PI3K pathway is an attractive candidate for the therapeutic targeting of tumors. Multiple kinases within the PI3Ks, AKT, and mTOR pathway have been selected for inhibition, and dual inhibitors have also been produced. Recently, the development of kinase inhibitors with enhanced specificity and improved pharmacokinetics has facilitated the investigation of PI3K pathway inhibition in clinical trials. Initial reports are encouraging, with tolerable toxicity profiles reported. PI3K inhibitors have provided some benefit as single-agent treatments of advanced solid tumors and the possibilities for enhanced effect with combination treatments look promising. In this chapter, we describe the PI3K inhibitors currently under investigation for the treatment of cancer and discuss the opportunities and obstacles that have been revealed by the latest preclinical and clinical studies.