Deregulations in mTOR-linked pathways increase the risk of developing cancer or have been identified in many human cancers

Deregulations include overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways, such as

Inappropriate signaling through members of the human epidermal growth factor receptor (HER/EGFR) family in lung, colon, and breast cancers1-3

Activation of the estrogen receptor (ER) through ligand-independent pathways linked to mTOR in breast cancer4

High levels of insulin-like growth factor (IGF-1) or expression of the IGF-1 receptor (IGF-1R) in breast, prostate, lung, thyroid, and kidney cancers, melanoma, and sarcoma5-11

Increased Ras or PI3-K signaling through activating mutations or loss-of-function mutations in tumor suppressor genes in pancreas, colon, thyroid, lung, leukemia, brain, gastric, breast, ovarian, prostate, endometrial, and oral squamous cell cancers and melanoma12-22

Formation of the Bcr-Abl fusion gene, which causes chronic myelogenous leukemia (CML)23

Deregulated signaling or cross-talk through mTOR-linked pathways can increase mTOR activity; mTOR inhibition could counteract this deregulated signaling

Combining an agent that directly targets mTOR with an agent that targets a deregulation in an mTOR-linked pathway could produce more profound anticancer activity than either agent alone, particularly in tumors that have lost function of the tumor suppressor gene, PTEN24