Recent results show aberrant Akt activation and FOXO3 inactivation confers 5-FU resistance [29], while the PI3K/mTOR inhibitor NVP-BEZ235 can effectively overcome 5-FU resistance through the up-regulation of PUMA expression, primarily through inactivation of PI3 K/Akt and activation of FOXO3, causing apoptosis even in cancer cells without functional p53 [29]. Here, PIK3CA is linked to cancer.