The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

Abstract

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

Automatic network generation describes differential gene data in user friendly and expeditiously analyzable network views

“…For example Figure 7B showed that AKT1 was using the adapter proteins CALM1 to influence the downstream signals IRS1. This is due to the used transcription factors, which shown to also mainly interact with AKT and similar networks missing ERK effects were painted [59,83,84] and was previously shown in literature [56,85]. Something similar was also shown for the ERK action on IRS1 [86].…”

“…The algorithm mainly shows two properties: (i) It nicely finds the interaction of phosphorylating and proteolytic signaling molecules, (ii) however it struggles to find interactions between signaling molecules and transcription factors. While the action of AKT on transcription factors is well described [59], the action of ERK on transcription factors could not be reconstructed as in the network of Klinger et al [34].…”

Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells

“…Numerous signaling molecules of the PI3K/Akt/mTOR pathway have oncogenic properties and constitutive activation of this signaling pathway is often involved in the progression of various human cancers (34,35). Contrary to tumor suppressor genes such as PTEN and p53 which can stimulate autophagy, oncogenes of PI3K and Akt have been confirmed to play an inhibiting role in autophagy activation.…”

Upregulation of microRNA‑18b induces phosphatase and tensin homolog to accelerate the migration and invasion abilities of ovarian cancer

“…In recent years, PTEN has gained particular attention for its critical role in multiple types of cancer. Numerous previous studies have demonstrated that low expression levels of PTEN were associated with poor prognosis and chemoresistance in OC (35,36).…”