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PI3K was discovered by Cantley and his colleague in 1985 and identified as an oncoprotein. His subsequent work identified the stimulators and downstream targets of the kinase[1, 10].He also found that the kinase consists of two subunits, a regulatory subunit p85 and a catalytic subunit p110. It is now known that there are 3 classes of PI3Ks. But only class IA is most related with cancer which consists of p85 and p110 (α, β and δ) while IB has p101 as a regulatory unit and p110γ as a catalytic subunit. Two major downstream proteins of PI3K have been identified: protein kinase B (Akt) and Rac 1. But Akt is more extensively studied as it regulates a broad range of target proteins. Akt is a serine/threonine kinase discovered by Blenis and his colleagues. There are three Akt isoforms including Akt1, Akt2 and Akt3. Akt 1 is related with cancer, Akt2 plays a key role in insulin-regulated glucose transportation and Akt 3 is special in brain development. In contrast to PI3K's narrow downstream targets, Akt regulates a broad range of downstream targets. Through them, cellular functions are changed to favour the development of cancer. Now even more downstream proteins are continuingly to be discoveried. One of Akt downstrem is mTOR. mTOR work in the forms of complexes with other proteins. There are two complexes of mTOR i.e. mTORC1 and mTORC2, which have different functions. mTORC1 consists of mTOR, raptor (regulatory associated protein of mTOR), mLST8 (also termed G-protein beta-subunit-like protein, a yeast homolog of LST8) and two negative regulators, PRAS40 (proline-rich Akt substrate 40 kDa) and Deptor. mTORC2 -----. The pathway PI3K/Akt/mTOR is highly emphasised in cancer therapy. In this pathway PI3K converts phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] and which act as a docking site. PIP3 recruits Akt and allow it to be phosphorylated by PDK1 at Thr308. Akt is also phosphorylated by mTORC2 at Ser 473 to reach fully activation.
Activation of the PI3K/Akt/mTOR pathway can be caused by both genetic defects and environmental factors. The former includes activating mutations of the major components of the pathway such as PIK3CA which encodes p110ï¡, PTEN and AKT[11-13]. It is not rare that two mutations together to activate the PI3K/Akt/mTOR pathway such as PTEN loss and PIK3CA activating mutation. Several growth factors are activators of the pathways via their receptors including GFR and Her2, PDGFR and IR/IGF-1 receptors[4, 8]. The activation of the PI3K/Akt pathway in cancer has been associated with mutation of these receptors. Obesity-associated cancer is now a major problem as obesity become epidemic and obesity is difficult to cure[15-19]. At present, one third of population is obese and another one third is overweight in Western country. Obesity increases cancer incidence and cause poorer prognosis via multiple signal pathways[7, 20]. Activation of the PI3K/Akt pathway is of importance in several obesity-associated cancers[21-25]. Several factors increased in the obesity contribute to the activation of PI3K/Akt /mTOR pathway including insulin/IGF-1, leptin and cytokines IL-6, IL-17 and TNF-alpha. These factors are known to activate the PI3K activity via their receptors[19, 26].
The central role of mTORC1 in carcinogenesis is also explained by its activation by other pathways independent of PI3K/Akt. However, mTORC1 is also regulated by MAPK pathway. Several other factors can also regulate mTOR independent of the PI3K/Akt pathway such as amino acid in blood, nutrients, oxygen and energy. The downstream targets of mTORC1 are S6K1 and 4E-BP1. S6K1, known as major ribosomal protein S6 kinase is phosphorylated at the sites, Thr229, Ser371 and Thr389. The phosphorylation of S6K1 leads to activation of the enzyme, resulting cell growth (size), proliferation and cell motility. It promotes translation initiation via phosphorylation of 40S ribosomal protein S6 and eIF4B. mTOR phosphorylates 4E-BP1 at the sites of Thr37 and Thr46. This will disrupt the function of 4E-BP1. 4E-BP1 usually binds tightly to the cap-binding protein eIF4E and represses cap-dependent mRNA translation. mTORC1 also limits catabolic processes such as autophagy. Recently it is found that mTORC1 can also promote cell migration via p70S6K pathway. Thus, the role of mTOR in cancer is much broader than initial concept that it regulates protein translation and promotes cancer cell growth.
Due to the important role of mTOR in cancer initiation and maintenance, inhibition of mTOR is highly regarded in cancer treatment. The first inhibitor used is rapamycin (sirolimus, Wyeth Ayerst Laboratories, Philadephia). Howevr, rapamycin is poor aqueous solubility and chemical instability, and this restricts its use clinically. Therefore, the analogues of rapamycin were developed including CCI-779 (Temsirolimus, Wyeth, madison, NJ, USA), RAD001 (Everolimus, Novartis, Basel, Switzerland), AP23573 (Deforolimus, ARIAD, Cambridge, MA, USA), SAR943 (Zotarolimus, ABT-578, Abbott Laboratories, Abbott Park, IL, USA. These are in clinical trials. The efficacy of mTOR inhibitors in clinical trials is not satisfactory. This is considered to be caused by increased Akt activity due to abolished feedback inhibition from mTOR. The downstream target of mTOR called S6K can feedback to inhibit IRS1. The application of rapmycin has resulted in increased PI3K/Akt activity. Except mTOR, Akt can promote carcinogenesis via many other target proteins. Some of them, if activated, are sufficient to cause cancer. For example, beta-catenin can be accumulated in the condition of activated Akt. Usually beta-catenin binds to GSK-3beta for degradation. pAKT can phosphorylate GSK-3beta and inactivate it, leading to beta-catenin to be released from the complex and translocated into nuclear. Beta-catenin regulates anumber genes to increase cell proliferation and decrease apoptosis.
Dual inhibitors of PI3K and mTOR are developed by several companies. They include Bez235 (Novartis), SF1126, XL765, GDC-0980 (Genentech inc.) and PI-103. The preclinical studies including tests in in vitro cell culture system and in vivo animal models demonstrated their superior effects than rapamycin. Many clinical trials have been carried out. It has been shown that these dual inhibitors are well tolerated by patients and have prolonged survival time.
A critical question is the crosstalk of the PI3K/Akt/mTOR pathway with other signal pathways. Usually multiple signal activation is found in many cancers[20, 31-33]. Activation of the PI3K/Akt pathway often co-exists with activation of other signal pathways such as MAPK, Stat3. For example, Ras mutation can activate both PI3K and MAPK pathways as Ras can directly bind to RAF protein and the PI3K subunit p110[34-35]. In this, dual inhibitor Bez235 was shown to be ineffective. When PI3K/Akt/mTOR is well inhibited, MAPK may be highly activated and the effect of Ras in the maintenance of tumour will not be abolished. A recent study has combined dual inhibitor of PI3K and mTOR with MAPK inhibitor and showed superior effect. In this study, a genetically engineered murine model of melanoma which has Ras mutation has been used for test. Among all tested therapies including 11 single agents and 16 regimens, only combinational use of Bez234 and AZD6244 is effective. This has been extended to breast cancer. The combinational therapy was effective against both Ras mutated model and non-Ras mutated model. Englman et al also demonstrated that Bez235 is effective against mutation of p110-induced lung cancer but was not effective against kras mutated lung cancer. However, combination of MEK inhibitor ARRY-142886 and Bez235 is effective . The combinational use of these two inhibitors have been shown to decrease Mcl-1, downstream target of PI3K and increase BIM, downstream target of MEK[38-40]. PI3K can also crosstalk to Wnt pathway via beta-catenin. A recent study showed that accumulation of beta-catenin via Wnt pathway conferred drug resistance to PI3K and Akt inhibitors in colon cancer. Akt can promote nuclear localisation of FOXO3a, which binds with beta-catenin to promote cancer cell metastasis. This can usually be inhibited by PI3K/Akt inhibitors. However in case of beta-catennin accumulation, PI3K/Akt inhibitors loss their effects. Therefore, following the test of dual inhibitor, an option could be the combinational implications of dual inhibitor of PI3K and mTOR with the inhibitor of other signal pathway such as those inhibit MAPK. Therefore, the signal pathways in an individual patient should be evaluated to decide if dual inhibitor is applicable to these patients.
A new kind of mTOR inhibitors have also been developed to overcome the feedback activation of PI3K including PP242, ku63794, wye354 and Torin1. They can also inhibit mTORC2. As mTORC2 can activate Akt at Ser473, inhibition of mTORC2 will leads to decreased pAkt. Further studies are needed to further evaluate their effect in comparison with dual inhibitors of PI3K and mTOR.
In summary, PI3K/Akt/mTOR is a major signal pathway activated in many cancers. mTOR play a central role and dual inhibitors can effectively inhibit the pathway. It may be effective on those cancers caused by mutation in the pathway. However, it is not effective in cancers caused by multiple signal pathways such as Kras mutation which activates both PI3K and MAPK pathways. In this, combination of a dual inhibitor of PI3K/mTOR and mapk inhibitor is effective. In addition the newly synthetic inhibitors against both mTORC1 and mTORC2 may have similar function as dual inhibitors of PI3K/mTOR. It needs to be further tested.