PIK3CA and cancer: Resistance to PI3K inhibitors has been observed in cancer cells in which upstream signalling is increased via upregulated secretion of the EGFR ligand amphiregulin [61], increased expression of receptor tyrosine kinases (RTKs) such as EGFR, HER3 and IGF1R/IR due to FOXO-mediated transcriptional upregulation [62], and activated NOTCH signalling [63].