INS and cancer: Because the binding of insulin to its receptors activates the PI3K/AKT pathway, which is known to stimulate mTOR activity, Kalaany and Sabatini's observations that tumor cells bearing constitutively activated PI3K mutations are proliferative in vitro in the absence of insulin or IGF-1 and form DR-resistant tumors in vivo [8] clearly suggest that cancer cell-autonomous alterations (e.g., activating mutations of PI3K) may ultimately determine the response of cancer cells to CR, DR, or CRMs.