+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Current Medicinal Chemistry 21(26): 3070-3080



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.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 051342384

Download citation: RISBibTeXText

PMID: 24735369


Related references

Activation of Pi3K/Akt/mTor Pathway and Dual Inhibitors of Pi3K and mTor in Endometrial Cancer. Current Medicinal Chemistry 21(26): 3070-3080, 2014

Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer. International Journal of Cancer 133(4): 984-996, 2013

G0S2 represses PI3K/mTOR signaling and increases sensitivity to PI3K/mTOR pathway inhibitors in breast cancer. Cell Cycle 16(21): 2146-2155, 2017

Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib. Cancer ChemoTherapy and Pharmacology 71(5): 1297-1307, 2013

Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors. Oncoscience 3(5-6): 164-172, 2016

Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models. Tumour Biology 37(1): 341-351, 2016

Tu1972 Dual PI3K/mTOR Inhibitors Induce Rapid Over-Activation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells Through Suppression of mTORC2. Gastroenterology 148(4): S-949-S-950, 2015

Defining optimal combinations of PI3K/Akt/mTOR and Ras/Raf/MAPK pathway inhibitors for use in endometrial cancer. Gynecologic Oncology 133: 127-128, 2014

Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood 115(22): 4455-4463, 2010

NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Research 68(19): 8022-8030, 2008

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. Bmc Cancer 17(1): 638, 2017

Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells. Cancer ChemoTherapy and Pharmacology 83(3): 451-461, 2019

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication. Journal of Biological Chemistry 293(16): 5808-5820, 2018

New inhibitors of the PI3K-Akt-mTOR pathway: insights into mTOR signaling from a new generation of Tor Kinase Domain Inhibitors (TORKinibs). Current Topics in Microbiology and Immunology 347: 241-262, 2010

Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2. Molecular Cancer Therapeutics 14(4): 1014-1023, 2015