Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer

Abstract

Endometrial cancer is the third most common cancer in women. Endometrial carcinomas (EC) are clinic histologically classified into two types. Type I tumours, which account for 80% of ECs, are estrogen-dependent and are low grade. Type II tumours are more aggressive with invasion into myometrium. Recently a new classification for endometrial cancer has been proposed based on molecular markers. Whether this classification is helpful for clinical management of endometrial cancer remains to be tested. At present, treatment outcomes of endometrial cancer are not satisfactory. Therefore, more effective approaches are sought. This review summarizes the recent studies about activation of PI3K/Akt pathway in EC and therapeutic implications of the inhibitors of the pathways with emphasis on dual inhibitors of PI3K and mTOR. Both genetic defects and environmental factors are involved in carcinogenesis and progression of EC via activation of multiple signal pathways including the PI3K/Akt pathway. Mutations of major components of the PI3K/Akt pathway are common in EC. Type I tumours usually have mutations in Ras, PTEN, PIK3CA, AKT1, beta-catenin and type II tumours have mutations in TP53. Environmental factor like obesity can also activate the PI3K/Akt pathway to increase the incidence of EC and to cause poorer prognosis. Therefore, inhibition of the PI3K/Akt pathway can be used for therapy of the disease. At present, mTOR inhibitors have been extensively studied and tested in clinical trials. A newly synthesised dual inhibitor of PI3K and mTOR BEZ235 has been shown to be more effective than mTOR inhibitor rapamycin. BEZ235 can inhibit feedback activation of PI3K/Akt pathway by rapamycin. It is promising to include effective PI3K/Akt inhibitors in current treatment regime of endometrial cancer to improve the therapeutic efficacy.