Understanding PI3K signalling in colorectal cancer: from function to therapy

Abstract

Aberrant phosphoinositide-3 kinase (PI3K) signalling is associated with the development and progression of several types of cancer including colorectal cancer (CRC) and accordingly a target for anti-cancer therapy. The canonical PI3K signalling cascade is initiated at the cell membrane where, upon receptor tyrosine kinase (RTK) activation by ligands such as EGF, PI3K is recruited and activated to convert phosphatidylinositol bisphosphate (PI(4,5)P2) to phosphatidylinositol trisphosphate (PI(3,4,5)P3), resulting in downstream signalling through phosphorylation and activation of AKT. This results in engagement of various downstream targets which are involved in the regulation of cellular processes such as proliferation, migration and apoptosis. PI3K signalling is negatively regulated by phosphatase PTEN, which removes the 3-phosphate from PI(3,4,5)P3. PIK3CA, encoding the catalytic subunit of PI3K, and PTEN are frequent targets of activating mutations or epigenetic silencing in CRC respectively. Furthermore, activating mutations of the MAPK pathway member KRAS has been implicated in oncogenic activation of PI3K signalling. Our knowledge of PI3K signalling derives from data assembled across a range of normal and cancer cell types however, a detailed survey of the downstream signalling cascade in CRC taking into account PI3K and MAPK pathway mutation status is presently lacking. Intriguingly, an alternate nuclear PI3K pathway has recently been identified in some cell types. Whether this nuclear PI3K cascade exists and is of importance in CRC remains unknown.

This thesis aims to (i) map the molecular signature of EGF induced PI3K/MAPK signalling in CRC with respect to tumour PI3K/MAPK mutation status, (ii) to test for the potential involvement of nuclear PI3K signalling in CRC and (iii) to investigate the clinical and therapeutic significance of the respective canonical and nuclear PI3K pathways.