The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

• Published in: Clinical cancer research Vol. 18; no. 21; pp. 5856 - 5864
• Main Authors: SLOMOVITZ, Brian M, COLEMAN, Robert L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2012
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Drug Therapy, Combination; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumors; Endometrium cancer; Targeting; Enzyme; Targeted therapy; Transferases; Akt protein kinase; Malignant tumor; Female genital diseases; 1-Phosphatidylinositol 3-kinase; Treatment; Mammalian target of rapamycin; Uterine diseases; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-0662

Endometrial cancer is the most common gynecologic malignancy in the United States. Overactivation of the PI3K/AKT/mTOR pathway, a signaling pathway that plays an important role in cellular growth and survival, has recently been implicated in endometrial cancer pathogenesis, and as such, inhibition of the PI3K/AKT/mTOR pathway is of therapeutic interest. Preclinical and clinical studies are proving useful in elucidating the antitumor effects of different PI3K/AKT/mTOR pathway inhibitors, and in defining which patient populations these inhibitors might be most effective in. For example, an increasing amount of preclinical data suggest that loss of PTEN or genetic alteration of PIK3CA may be indicators of sensitivity to PI3K/AKT/mTOR pathway inhibition, while activating KRAS mutations may predict resistance. In the latter case, combined inhibition of the RAS/RAF/MEK and PI3K/AKT/mTOR pathways has been suggested as a therapeutic strategy. In addition, the PI3K/AKT/mTOR pathway has been implicated in conferring resistance to conventional therapies, and so PI3K/AKT/mTOR pathway inhibitors in combination with hormonal and/or cytotoxic agents are being evaluated. In conclusion, preclinical models are providing insights into the antitumor activity of PI3K/AKT/mTOR pathway inhibition, and are helping define patient populations most likely to benefit from these therapies. Clinical validation of these findings is ongoing.