We have initiated preclinical studies to understand mechanistically the role of inhibitors of the PI3K-AKT-mTOR axis in relation to regorafenib treatment in colorectal carcinoma cell lines, and if promising, will proceed to a clinical trial of addition of a PI3K or AKT inhibitor in patients with metastatic colorectal carcinoma who have demonstrated refractoriness to regorafenib, selected on the basis of up regulation of the PI3K/AKT axis. Here, PIK3CA is linked to colorectal carcinoma.