View source for PI3K/AKT/mTOR pathway

{{Short description|Cell cycle regulation pathway}}
[[Image:MTOR-pathway-v1.7.svg|thumb|right|420px|mTOR signaling pathway.]]
The '''PI3K/AKT/mTOR pathway''' is an intracellular signaling pathway important in regulating the [[cell cycle]]. Therefore, it is directly related to cellular [[G0 phase|quiescence]], [[Cell proliferation|proliferation]], [[cancer]], and longevity. [[Phosphoinositide 3-kinase|PI3K]] activation [[phosphorylate]]s and activates [[Protein kinase B|AKT]], localizing it in the [[plasma membrane]].<ref>{{cite journal | vauthors = King D, Yeomanson D, Bryant HE | title = PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma | journal = Journal of Pediatric Hematology/Oncology | volume = 37 | issue = 4 | pages = 245–51 | date = May 2015 | pmid = 25811750 | doi = 10.1097/MPH.0000000000000329 | s2cid = 42323379 }}</ref>  AKT can have a number of downstream effects such as activating [[CREB]],<ref name="Peltier_2007">{{cite journal | vauthors = Peltier J, O'Neill A, Schaffer DV | title = PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation | journal = Developmental Neurobiology | volume = 67 | issue = 10 | pages = 1348–61 | date = September 2007 | pmid = 17638387 | doi = 10.1002/dneu.20506 | s2cid = 16337839 }}</ref> inhibiting [[p27 (gene)|p27]],<ref name=Rafalski_2011/> localizing [[FOXO]] in the cytoplasm,<ref name=Rafalski_2011/> activating [[Phosphatidylinositol|PtdIns]]-3ps,<ref name="Man_2003"/> and activating [[Mechanistic target of rapamycin|mTOR]]<ref name=Rafalski_2011/> which can affect transcription of p70 or 4EBP1.<ref name=Rafalski_2011/> There are many known factors that enhance the PI3K/AKT pathway including [[Epidermal growth factor|EGF]],<ref name="Ojeda_2011">{{cite journal | vauthors = Ojeda L, Gao J, Hooten KG, Wang E, Thonhoff JR, Dunn TJ, Gao T, Wu P | display-authors = 6 | title = Critical role of PI3K/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23414 | year = 2011 | pmid = 21887250 | pmc = 3160859 | doi = 10.1371/journal.pone.0023414 | bibcode = 2011PLoSO...623414O | doi-access = free }}</ref> [[Sonic hedgehog (protein)|shh]],<ref name="Peltier_2007"/> [[IGF-1]],<ref name="Peltier_2007"/> [[insulin]],<ref name=Rafalski_2011/> and [[calmodulin]].<ref name="Man_2003"/> Both [[leptin]] and insulin recruit PI3K signalling for metabolic regulation.<ref name="pmid30618188">{{cite journal | vauthors=Garcia-Galiano D, Borges BC, Allen SJ, Elias CF | title=PI3K signalling in leptin receptor cells: Role in growth and reproduction| journal=[[Journal of Neuroendocrinology]] | volume=31 | issue = 5| pages=e12685 | year=2019 |  doi = 10.1111/jne.12685 | pmc = 6533139 | pmid=30618188 }}</ref> The pathway is antagonized by various factors including [[Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase|PTEN]],<ref name="ReferenceC">{{cite journal | vauthors = Wyatt LA, Filbin MT, Keirstead HS | title = PTEN inhibition enhances neurite outgrowth in human embryonic stem cell-derived neuronal progenitor cells | journal = The Journal of Comparative Neurology | volume = 522 | issue = 12 | pages = 2741–55 | date = August 2014 | pmid = 24610700 | doi = 10.1002/cne.23580 | s2cid = 205683500 }}</ref> [[GSK3B]],<ref name="Peltier_2007"/> and HB9.<ref name="Ojeda_2011"/>
In many cancers, this pathway is overactive, thus reducing [[apoptosis]] and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of [[adult stem cells]], [[neural stem cells]] specifically.<ref name="Peltier_2007"/> It is the difficulty in finding an appropriate amount of proliferation versus differentiation that researchers are trying to determine in order to utilize this balance in the development of various therapies.<ref name="Peltier_2007"/> Additionally, this pathway has been found to be a necessary component in neural [[long term potentiation]].<ref name="Man_2003"/><ref name = "Sui_2008">{{cite journal | vauthors = Sui L, Wang J, Li BM | title = Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex | journal = Learning & Memory | volume = 15 | issue = 10 | pages = 762–76 | date = October 2008 | pmid = 18832563 | doi = 10.1101/lm.1067808 | doi-access = free }}</ref>
==Proliferation of neural stem cells==
===Response to glucose===
Neural stem cells (NSCs) in the brain must find a balance between maintaining their [[multipotency]] by self renewing and proliferating as opposed to differentiating and becoming quiescent. The PI3K/AKT pathway is crucial in this decision making process. NSCs are able to sense and respond to changes in the brain or throughout the organism. When blood glucose levels are elevated acutely, insulin is released from the pancreas. Activation of insulin receptors activates the PI3K/AKT pathway, which promotes proliferation.<ref name=Rafalski_2011>{{cite journal | vauthors = Rafalski VA, Brunet A | title = Energy metabolism in adult neural stem cell fate | journal = Progress in Neurobiology | volume = 93 | issue = 2 | pages = 182–203 | date = February 2011 | pmid = 21056618 | doi = 10.1016/j.pneurobio.2010.10.007 | s2cid = 16305263 }}</ref> In this way, when there is high glucose and abundant energy in the organism, the PI3K/AKT pathway is activated and NSCs tend to proliferate. When there are low amounts of available energy, the PI3K/AKT pathway is less active and cells adopt a quiescent state.
This occurs, in part, when AKT phosphorylates FOXO, keeping FOXO in the cytoplasm.<ref name=Rafalski_2011/> FOXO, when dephosphorylated, can enter the nucleus and work as a [[transcription factor]] to promote the expression of various tumor suppressors such as [[p27 (gene)|p27]] and [[p21]].<ref name=Rafalski_2011/> These tumor suppressors push the NSC to enter quiescence. FOXO knockouts lose the ability for cells to enter a quiescent state as well as cells losing their neural stem cell character, possibly entering a cancer like state.<ref name=Rafalski_2011/>
===PTEN===
The PI3K/AKT pathway has a natural inhibitor called Phosphatase and tensin homolog ([[PTEN (gene)|PTEN]]) whose function is to limit proliferation in cells, helping to prevent cancer. Knocking out PTEN has been shown to increase the mass of the brain because of the unregulated proliferation that occurs.<ref name=Rafalski_2011/>
PTEN works by dephosphorylating PIP3 to PIP2 which limits AKTs ability to bind to the membrane, decreasing its activity. PTEN deficiencies can be compensated downstream to rescue differentiation or quiescence. Knocking out PTEN is not as serious as knocking out FOXO for this reason.<ref name=Rafalski_2011/>
===CREB===
The cAMP response element [[CREB]] is closely related to the cell decision to proliferate or not. Cells that are forced to overexpress AKT increase the amount of CREB and proliferation compared to wild type cells. These cells also express less [[glial]] and neural cell markers such as [[Glial fibrillary acidic protein|GFAP]] or [[β-tubulin]].<ref name="Peltier_2007"/> This is because CREB is a transcription factor that influences the transcription of [[cyclin A]] which promotes proliferation.<ref name="Peltier_2007"/> For example, adult [[hippocampal]] neural progenitor cells need abeyance as stem cells to differentiate later. This is regulated by [[Sonic hedgehog|Shh]]. Shh works through a slow protein synthesis dependence, which stimulates other cascades that work synergistically with the PI3K/AKT pathway to induce proliferation. Then, the other pathway can be turned off and the effects of the PI3K/AKT pathway become insufficient in stopping differentiation.<ref name="Peltier_2007"/> The specifics of this pathway are unknown.
==Roles in cancer==
===Ovarian cancer===
[[Phosphoinositide 3-kinase|PI3K]]/ [[Protein kinase B|AKT]]/[[Mechanistic target of rapamycin|mTOR]] pathway is a central regulator of [[ovarian cancer]]. [[PIM1|PIM]] kinases are over expressed in many types of cancers and they also contribute to the regulation of [[ovarian cancer]]. PIM are directly and indirectly found to activate mTOR and its upstream effectors like AKT. Besides, PIM kinases can cause phosphorylation of IRS, which can alter PI3K. This indicates the close interaction of PIM with PI3K/ AKT/mTOR cascade and its components. Similarly, AKT has also been reported to perform the BAD phosphorylation in OC cells. PIM and the PI3K/AKT/mTOR network both can inhibit the [[P21]] and [[P27 (gene)|P27]] expressions in OC cells. These data suggest a strong possibility of interaction and relevance of PIM kinases and the PI3K/AKT/mTOR network in the regulation of ovarian cancer.<ref>{{cite journal | vauthors = Aziz AU, Farid S, Qin K, Wang H, Liu B | title = PIM Kinases and Their Relevance to the PI3K/AKT/mTOR Pathway in the Regulation of Ovarian Cancer | journal = Biomolecules | volume = 8 | issue = 1 | pages = 7 | date = February 2018 | pmid = 29401696 | pmc = 5871976 | doi = 10.3390/biom8010007 | doi-access = free }}</ref> However, targeting this pathway in ovarian cancer has been challenging with several trials failing to achieve sufficient clinical benefit.<ref>{{Cite journal|last1=Ciccone|first1=Marcia A.|last2=Maoz|first2=Asaf|last3=Casabar|first3=Jennifer K.|last4=Machida|first4=Hiroko|last5=Mabuchi|first5=Seiji|last6=Matsuo|first6=Koji|date=July 2016|title=Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature|journal=Expert Opinion on Investigational Drugs|volume=25|issue=7|pages=781–796|doi=10.1080/13543784.2016.1181748|issn=1744-7658|pmid=27101098|s2cid=28717797|pmc=7534810}}</ref><ref>{{Cite journal|last1=Maoz|first1=Asaf|last2=Ciccone|first2=Marcia A.|last3=Matsuzaki|first3=Shinya|last4=Coleman|first4=Robert L.|last5=Matsuo|first5=Koji|date=2019-11-22|title=Emerging serine-threonine kinase inhibitors for treating ovarian cancer|journal=Expert Opinion on Emerging Drugs|volume=24|issue=4|pages=239–253|doi=10.1080/14728214.2019.1696773|issn=1744-7623|pmid=31755325|s2cid=208227849|pmc=7526049}}</ref>
===Breast cancer===
In many kinds of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities. The most common known aberrations include the [[PIK3CA]] gene mutation and the loss-of-function mutations or epigenetic silencing of  PTEN.<ref name = "Raphael_2018">{{cite journal | vauthors = Raphael J, Desautels D, Pritchard KI, Petkova E, Shah PS | title = Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis | journal = European Journal of Cancer | volume = 91 | pages = 38–46 | date = March 2018 | pmid = 29331750 | doi = 10.1016/j.ejca.2017.12.010 }}</ref> The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is activated in approximately 30–40% of BC cases. In [[triple-negative breast cancer]] (TNBC), oncogenic activation of the PI3K/AKT/mTOR pathway can happen as a function of overexpression of upstream regulators like [[Epidermal growth factor receptor|EGFR]], activating mutations of [[PIK3CA]], loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K.<ref name = "Costa_2018">{{cite journal | vauthors = Costa RL, Han HS, Gradishar WJ | title = Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review | journal = Breast Cancer Research and Treatment | volume = 169 | issue = 3 | pages = 397–406 | date = June 2018 | pmid = 29417298 | doi = 10.1007/s10549-018-4697-y | s2cid = 19888056 }}</ref> It is consistent with the hypothesis that PI3K inhibitors can overcome resistance to endocrine therapy when it is acquired{{cn|date=October 2023}}
===Urothelial cancer===
PIK3CA frequently have gain of function mutations in urothelial cancer.<ref>{{cite journal | vauthors = Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J | display-authors = 6 | title = NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations | journal = Cancer Research | volume = 68 | issue = 19 | pages = 8022–30 | date = October 2008 | pmid = 18829560 | doi = 10.1158/0008-5472.CAN-08-1385 | doi-access = free }}</ref> Similar to PI3Ka, PI3Kb is expressed in many different cells, and it is mainly involved in the activation of platelets and development of thrombotic diseases. Studies have shown that PI3Kb contribute to tumor proliferation as well. Specifically, it has an important role in tumorigenesis in PTEN-negative cancers.<ref>{{cite journal | vauthors = Liu ST, Hui G, Mathis C, Chamie K, Pantuck AJ, Drakaki A | title = The Current Status and Future Role of the Phosphoinositide 3 Kinase/AKT Signaling Pathway in Urothelial Cancer: An Old Pathway in the New Immunotherapy Era | journal = Clinical Genitourinary Cancer | volume = 16 | issue = 2 | pages = e269–e276 | date = April 2018 | pmid = 29199023 | doi = 10.1016/j.clgc.2017.10.011 | s2cid = 4533538 }}</ref> It's reported that interfering with the gene for PI3Kb might be a therapeutic approach for high-risk bladder cancers with mutant PTEN and [[E-cadherin]] loss. Specific isoform inhibitors to PI3Kb is a potential treatment for PTEN-deficient cancers.<ref>{{cite journal | vauthors = Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, Pink MM, Proctor JL, Lussier J, Martin CM, Hoyt JG, Tillotson B, Murphy EL, Lim AR, Thomas BD, Macdougall JR, Ren P, Liu Y, Li LS, Jessen KA, Fritz CC, Dunbar JL, Porter JR, Rommel C, Palombella VJ, Changelian PS, Kutok JL | display-authors = 6 | title = PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models | journal = Chemistry & Biology | volume = 20 | issue = 11 | pages = 1364–74 | date = November 2013 | pmid = 24211136 | doi = 10.1016/j.chembiol.2013.09.017 | doi-access = free }}</ref>
===Prostate cancer===
The PI3K pathway is a major source of drug resistance in [[prostate cancer]]. This is particularly true in castration-resistant prostate cancer, where tumours become resistant to [[Androgen deprivation therapy|androgen-deprivation therapy]], which block the tumours ability to utilise the hormone [[androgen]] to grow.<ref>{{Cite journal|last1=Park|first1=Soonbum|last2=Kim|first2=Young Sik|last3=Kim|first3=Davis Yeon|last4=So|first4=Insuk|last5=Jeon|first5=Ju-Hong|date=December 2018|title=PI3K pathway in prostate cancer: All resistant roads lead to PI3K|journal=Biochimica et Biophysica Acta (BBA) - Reviews on Cancer|volume=1870|issue=2|pages=198–206|doi=10.1016/j.bbcan.2018.09.001|issn=1879-2561|pmid=30300679|s2cid=52947672}}</ref> This is due to a complex feedback mechanism which exists between the [[androgen receptor]] and the PI3K pathway.<ref>{{Cite journal|last1=Carver|first1=Brett S.|last2=Chapinski|first2=Caren|last3=Wongvipat|first3=John|last4=Hieronymus|first4=Haley|last5=Chen|first5=Yu|last6=Chandarlapaty|first6=Sarat|last7=Arora|first7=Vivek K.|last8=Le|first8=Carl|last9=Koutcher|first9=Jason|last10=Scher|first10=Howard|last11=Scardino|first11=Peter T.|date=2011-05-17|title=Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer|journal=Cancer Cell|volume=19|issue=5|pages=575–586|doi=10.1016/j.ccr.2011.04.008|issn=1878-3686|pmc=3142785|pmid=21575859}}</ref> As in other tumour types, mutations in key genes of this pathway can lead to hyperactivation of this pathway, for example in PIK3CA,<ref>{{Cite journal|last1=Zahari|first1=Muhammad Saddiq|last2=Wu|first2=Xinyan|last3=Blair|first3=Brian G.|last4=Pinto|first4=Sneha M.|last5=Nirujogi|first5=Raja S.|last6=Jelinek|first6=Christine A.|last7=Malhotra|first7=Radhika|last8=Kim|first8=Min-Sik|last9=Park|first9=Ben Ho|last10=Pandey|first10=Akhilesh|date=2015-09-04|title=Activating Mutations in PIK3CA Lead to Widespread Modulation of the Tyrosine Phosphoproteome|journal=Journal of Proteome Research|volume=14|issue=9|pages=3882–3891|doi=10.1021/acs.jproteome.5b00302|issn=1535-3907|pmc=4641567|pmid=26267517}}</ref><ref>{{Cite journal|last1=Pearson|first1=Helen B.|last2=Li|first2=Jason|last3=Meniel|first3=Valerie S.|last4=Fennell|first4=Christina M.|last5=Waring|first5=Paul|last6=Montgomery|first6=Karen G.|last7=Rebello|first7=Richard J.|last8=Macpherson|first8=Arthi A.|last9=Koushyar|first9=Sarah|last10=Furic|first10=Luc|last11=Cullinane|first11=Carleen|date=June 2018|title=Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth|journal=Cancer Discovery|volume=8|issue=6|pages=764–779|doi=10.1158/2159-8290.CD-17-0867|issn=2159-8290|pmid=29581176|doi-access=free}}</ref> Increases in the copy number of PIK3CA and increased [[Messenger RNA|mRNA]] expression also increases pathway activation in prostate cancers among others.<ref>{{Cite journal|last1=Agell|first1=Laia|last2=Hernández|first2=Silvia|last3=Salido|first3=Marta|last4=de Muga|first4=Silvia|last5=Juanpere|first5=Nuria|last6=Arumí-Uria|first6=Montserrat|last7=Menendez|first7=Silvia|last8=Lorenzo|first8=Marta|last9=Lorente|first9=José A.|last10=Serrano|first10=Sergio|last11=Lloreta|first11=Josep|date=March 2011|title=PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events|journal=Modern Pathology|volume=24|issue=3|pages=443–452|doi=10.1038/modpathol.2010.208|issn=1530-0285|pmid=21113138|s2cid=27405431|doi-access=free}}</ref> [[Copy-number variation|Gains]] in the nearby genetic region 3q26.31-32 have been shown to co-occur with a number of nearby PI3K family members including ''[[P110α|PIK3CA]], [[PIK3CB]]'' and ''[[PIK3R4]]'', leading to transcriptional changes in ''[[PIK3C2G]], PIK3CA, PIK3CB, PIK3R4'' as well as pathways associated with [[cell proliferation]].<ref name=":0">{{Cite journal|last1=Simpson|first1=Benjamin S.|last2=Camacho|first2=Niedzica|last3=Luxton|first3=Hayley J.|last4=Pye|first4=Hayley|last5=Finn|first5=Ron|last6=Heavey|first6=Susan|last7=Pitt|first7=Jason|last8=Moore|first8=Caroline M.|last9=Whitaker|first9=Hayley C.|date=2020-08-14|title=Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype|journal=Communications Biology|language=en|volume=3|issue=1|page=440|doi=10.1038/s42003-020-01175-x|pmid=32796921|pmc=7429505|s2cid=221118233|issn=2399-3642|doi-access=free}}</ref> These large spanning gains associate with [[Gleason grading system|Gleason grade]], [[Cancer staging|tumour stage]], [[Lymph node|lymph node metastasis]] and other aggressive clinical features.<ref name=":0" /> In patients treated with PI3K inhibitors, those with copy number gains in ''PIK3CB'' appear to have increased drug susceptibility.<ref>{{Cite journal|last1=Bono|first1=Johann de|last2=Arkenau|first2=Hendrik-Tobias|last3=Mateo|first3=Joaquin|last4=Infante|first4=Jeffrey R.|last5=Burris|first5=Howard A.|last6=Bang|first6=Yung-Jue|last7=Eder|first7=Joseph|last8=Sharma|first8=Sunil|last9=Chung|first9=Hyun C.|last10=Decordova|first10=Shaun|last11=Swales|first11=Karen E.|date=2015-08-01|title=Abstract CT328: Exploratory genetic analysis of tumors from a phase I/II dose escalation study of GSK2636771 in patients (pts) with PTEN deficient advanced tumors|url=https://cancerres.aacrjournals.org/content/75/15_Supplement/CT328|journal=Cancer Research|language=en|volume=75|issue=15 Supplement|pages=CT328|doi=10.1158/1538-7445.AM2015-CT328|issn=0008-5472}}</ref>
==Therapies==
===PI3K inhibitor===
[[Phosphoinositide 3-kinase|PI3K]] inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes.<ref name = "Raphael_2018" /> Different PI3K inhibitors exhibit different effect against various PI3K types. Class IA pan-PI3K inhibitors have been more extensively studied than isoform specific inhibitors; [[Pictilisib]] is another pan-PI3K inhibitor with greater subunitα-inhibitor activity than buparlisib.<ref name = "Costa_2018" /> [[Idelalisib]] is the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib is approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies.<ref>{{cite journal | vauthors = Greenwell IB, Ip A, Cohen JB | title = PI3K Inhibitors: Understanding Toxicity Mechanisms and Management | journal = Oncology | volume = 31 | issue = 11 | pages = 821–8 | date = November 2017 | pmid = 29179250 }}</ref> [[Duvelisib]] is approved for [[Chronic lymphocytic leukemia|relapsed/refractory chronic lymphocytic leukemia]]/small lymphocytic lymphoma (CLL/SLL),  and relapsed/refractory follicular lymphoma, both indications for patients who have received at least two prior therapies.<ref>{{cite web|title=duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) |url= https://www.fda.gov/drugs/resources-information-approved-drugs/duvelisib-copiktra-verastem-inc-adult-patients-relapsed-or-refractory-chronic-lymphocytic-leukemia |website= U.S. Food and Drug Administration |access-date=23 October 2018 }}</ref>
===Akt inhibitor===
[[AKT]] is downstream to [[PI3K]] and is inhibited by Ipatasertib.<ref name = "Costa_2018" /> Akt is an AGC-family kinase and a central, integral signaling node of the [[PAM (gene)|PAM]] pathway. There are three Akt isozymes, Akt1, Akt2 and Akt3. Small-molecule inhibitors of Akt1 could be especially useful to target tumors with a high prevalence of Akt1 E17K activating mutations, which is observed in 4–6% of breast cancers and 1–2% of colorectal cancer.<ref name = "Huck_2017">{{cite journal | vauthors = Huck BR, Mochalkin I | title = Recent progress towards clinically relevant ATP-competitive Akt inhibitors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 27 | issue = 13 | pages = 2838–2848 | date = July 2017 | pmid = 28506751 | doi = 10.1016/j.bmcl.2017.04.090 }}</ref>  Research towards [[Akt]] inhibition has focused on inhibition of two distinct binding sites:
* the allosteric pocket of the inactive enzyme, and
* the ATP binding site.
Allosteric Akt inhibitors, highlighted by MK-2206, have been extensively evaluated in a clinical setting; Recently, additional allosteric Akt inhibitors have been identified. ARQ-092, is a potent pan-Akt inhibitor which can inhibit tumor growth preclinically and is currently in Phase I clinical studies.<ref name = "Huck_2017" />
===mTOR inhibitor===
There is significant correlation of phosphorylated [[mTOR]] with the survival rate for patients with stages I and II TNBC. A patient-derived xenograft TNBC model testing the mTOR inhibitor rapamycin showed 77–99% tumor-growth inhibition, which is significantly more than has been seen with doxorubicin; protein phosphorylation studies indicated that constitutive activation of the mTOR pathway decreased with treatment.<ref name = "Costa_2018" />
===Dual PI3K/AKT/mTOR inhibitors===
It has been hypothesized that blockage of the PI3K/AKT/mTOR pathway can lead to increased antitumor activity in TNBC. Preclinical data have shown that the combination of compounds targeting different cognate molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. On the basis of these findings, new compounds targeting different components of the PI3K/AKT/mTOR pathway simultaneously continue to be developed. For example, gedatolisib inhibits mutant forms of PI3K-α with elevated kinase activity at concentrations equivalent to the IC50 for wild-type PI3K-α. PI3K-β, -δ and -γ isoforms were inhibited by gedatolisib at concentrations approximately 10-fold higher than those observed for PI3K-α.<ref name = "Costa_2018" /> Another advantage of simultaneously targeting PI3K and mTOR is the ensuing more robust inhibition of receptor tyrosine kinase-positive feedback loops seen with isolated [[PI3K]] inhibition.<ref>{{cite journal | vauthors = Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL | title = Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 8 | pages = 2718–23 | date = February 2012 | pmid = 21368164 | pmc = 3286932 | doi = 10.1073/pnas.1018001108 | bibcode = 2012PNAS..109.2718C | doi-access = free }}</ref> Gedatolisib is currently under development for the treatment of TNBC, in combination with PTK7 antibody–drug conjugate. Apitolisib (GDC-0980) is a PI3K inhibitor (subunits α, δ, and γ) that also targets mTORC <ref>{{cite journal | vauthors = Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP, Radvanyi F | title = Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder | journal = Oncogene | volume = 14 | issue = 25 | pages = 3059–66 | date = June 1997 | pmid = 9223669 | doi = 10.1038/sj.onc.1201154 | doi-access = free }}</ref>
=== PI3K pathway co-targeted therapy ===
There are numerous cell signalling pathways that exhibit cross-talk with the PI3K pathway, potentially allowing cancer cells to escape inhibition of PI3K.<ref>{{Cite journal|last1=Heavey|first1=Susan|last2=O'Byrne|first2=Kenneth J.|last3=Gately|first3=Kathy|date=April 2014|title=Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC|journal=Cancer Treatment Reviews|volume=40|issue=3|pages=445–456|doi=10.1016/j.ctrv.2013.08.006|issn=1532-1967|pmid=24055012}}</ref> As such, inhibition of the PI3K pathway alongside other targets could offer a synergistic response, such as that seen with PI3K and MEK co-targeted inhibition in lung cancer cells.<ref>{{Cite journal|last1=Heavey|first1=Susan|last2=Cuffe|first2=Sinead|last3=Finn|first3=Stephen|last4=Young|first4=Vincent|last5=Ryan|first5=Ronan|last6=Nicholson|first6=Siobhan|last7=Leonard|first7=Niamh|last8=McVeigh|first8=Niall|last9=Barr|first9=Martin|last10=O'Byrne|first10=Kenneth|last11=Gately|first11=Kathy|date=2016-11-29|title=In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC|journal=Oncotarget|volume=7|issue=48|pages=79526–79543|doi=10.18632/oncotarget.12755|issn=1949-2553|pmc=5346733|pmid=27765909}}</ref> More recently, co-targeting the PI3K pathway with PIM kinases has been suggested, with numerous pre-clinical studies suggesting the potential benefit of this approach.<ref>{{Cite journal|last1=Luszczak|first1=Sabina|last2=Kumar|first2=Christopher|last3=Sathyadevan|first3=Vignesh Krishna|last4=Simpson|first4=Benjamin S.|last5=Gately|first5=Kathy A.|last6=Whitaker|first6=Hayley C.|last7=Heavey|first7=Susan|date=2020|title=PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer|journal=Signal Transduction and Targeted Therapy|volume=5|pages=7|doi=10.1038/s41392-020-0109-y|issn=2059-3635|pmc=6992635|pmid=32025342}}</ref><ref>{{Cite journal|last1=Malone|first1=Tom|last2=Schäfer|first2=Lea|last3=Simon|first3=Nathalie|last4=Heavey|first4=Susan|last5=Cuffe|first5=Sinead|last6=Finn|first6=Stephen|last7=Moore|first7=Gillian|last8=Gately|first8=Kathy|date=March 2020|title=Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer|journal=Pharmacology & Therapeutics|volume=207|pages=107454|doi=10.1016/j.pharmthera.2019.107454|issn=1879-016X|pmid=31836451|s2cid=209357486|url=https://discovery.ucl.ac.uk/id/eprint/10088376/1/1-s2.0-S0163725819302062-main.pdf}}</ref> Development of panels of cell lines that are resistant to inhibition of the PI3K pathway may lead to the identification of future co-targets, and better understanding of which pathways may compensate for loss of PI3K signalling following drug treatment.<ref>{{Cite journal|last1=Heavey|first1=Susan|last2=Dowling|first2=Paul|last3=Moore|first3=Gillian|last4=Barr|first4=Martin P.|last5=Kelly|first5=Niamh|last6=Maher|first6=Stephen G.|last7=Cuffe|first7=Sinead|last8=Finn|first8=Stephen P.|last9=O'Byrne|first9=Kenneth J.|last10=Gately|first10=Kathy|date=26 January 2018|title=Development and characterisation of a panel of phosphatidylinositide 3-kinase - mammalian target of rapamycin inhibitor resistant lung cancer cell lines|journal=Scientific Reports|volume=8|issue=1|pages=1652|doi=10.1038/s41598-018-19688-1|issn=2045-2322|pmc=5786033|pmid=29374181|bibcode=2018NatSR...8.1652H}}</ref> Combined PI3K inhibition with more traditional therapies such as chemotherapy may also offer improved response over inhibition of PI3K alone.<ref>{{Cite journal|last1=Heavey|first1=Susan|last2=Godwin|first2=Peter|last3=Baird|first3=Anne-Marie|last4=Barr|first4=Martin P.|last5=Umezawa|first5=Kazuo|last6=Cuffe|first6=Sinéad|last7=Finn|first7=Stephen P.|last8=O'Byrne|first8=Kenneth J.|last9=Gately|first9=Kathy|date=October 2014|title=Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC|journal=Cancer Biology & Therapy|volume=15|issue=10|pages=1367–1377|doi=10.4161/cbt.29841|issn=1555-8576|pmc=4130730|pmid=25025901}}</ref>
===Neural stem cells===
The type of growth factor signaling can effect whether or not NSCs differentiate into motor neurons or not. Priming a media with FGF2 lowers the activity of the PI3K/AKT pathway, which activates GSK3β. This increases expression of HB9.<ref name="Ojeda_2011"/> Directly inhibiting PI3K in NSCs leads to a population of cells that are purely HB9+ and differentiate at an elevated efficiency into motor neurons. Grafting these cells into different parts of rats generates [[motor neurons]] regardless of the transplanted cells' microenvironment.<ref name="Ojeda_2011"/> Following injury, neural stem cells enter a repair phase and express high levels of PI3K to enhance proliferation. This is better for survival of the neurons as a whole but is at the expense of generating motor neurons. Therefore, it can be difficult for injured motor neurons to recover their ability.<ref name="Ojeda_2011"/> It is the purpose of modern research to generate neural stem cells that can proliferate but still differentiate into motor neurons. Lowering the effect of the PI3K pathway and increasing the effect of GSK3β and HB9 in NSCs is a potential way of generating these cells.<ref name="Ojeda_2011"/>
===PTEN inhibitors===
PTEN is a tumor suppressor that inhibits the PI3K/AKT pathway. PTEN inhibitors, such as bisperoxovanadium,<ref>{{cite journal | vauthors = Schmid AC, Byrne RD, Vilar R, Woscholski R | title = Bisperoxovanadium compounds are potent PTEN inhibitors | journal = FEBS Letters | volume = 566 | issue = 1–3 | pages = 35–8 | date = May 2004 | pmid = 15147864 | doi = 10.1016/j.febslet.2004.03.102 | doi-access = free }}</ref> can enhance the PI3K/AKT pathway to promote cell migration,<ref>{{cite journal | vauthors = Mihai C, Bao S, Lai JP, Ghadiali SN, Knoell DL | title = PTEN inhibition improves wound healing in lung epithelia through changes in cellular mechanics that enhance migration | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 302 | issue = 3 | pages = L287-99 | date = February 2012 | pmid = 22037358 | pmc = 3289272 | doi = 10.1152/ajplung.00037.2011 }}</ref> survival<ref>{{cite journal | vauthors = Lai JP, Dalton JT, Knoell DL | title = Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair | journal = British Journal of Pharmacology | volume = 152 | issue = 8 | pages = 1172–84 | date = December 2007 | pmid = 17922022 | pmc = 2189995 | doi = 10.1038/sj.bjp.0707501 }}</ref> and proliferation.<ref name="ReferenceC"/> While there are some concerns over possible cell cycle dysregulation and tumorigenesis, temporary and moderate PTEN inhibition may confer [[neuroprotection]] against traumatic brain injury<ref name=Walker2012>{{cite journal | vauthors = Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, Xu XM | title = Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e30012 | year = 2012 | pmid = 22253859 | pmc = 3254642 | doi = 10.1371/journal.pone.0030012 | bibcode = 2012PLoSO...730012W | doi-access = free }}</ref> and improve CNS recovery by reestablishing lost connections by [[axonogenesis]].<ref name="ReferenceC"/> Medicinal value of PTEN inhibitors remains to be determined.{{cn|date=October 2023}}
==Long-term potentiation==
In order for [[long-term potentiation]] (LTP) to occur, there must be stimulation of [[NMDA receptors]], which causes [[AMPA receptors]] to be inserted [[postsynaptic]]ally. PI3K binds to AMPA receptors in a conserved region to orient the receptors in the membrane, specifically at the GluR subunit.<ref name=Man_2003>{{cite journal | vauthors = Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D'Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu F, Wymann MP, MacDonald JF, Wang YT | display-authors = 6 | title = Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons | journal = Neuron | volume = 38 | issue = 4 | pages = 611–24 | date = May 2003 | pmid = 12765612 | doi = 10.1016/s0896-6273(03)00228-9 | s2cid = 17419450 | doi-access = free }}</ref> PI3K activity increases in response to [[calcium ions]] and [[CaM]]. Additionally, AKT localizes PtdIns-3Ps in the post synapse, which recruits docking proteins such as [[tSNARE]] and Vam7. This directly leads to the docking of AMPA in the post synapse.<ref name="Man_2003"/>  mTOR activated p70S6K and inactivated 4EBP1 which changes gene expression to allow LTP to occur.<ref name = "Sui_2008" /> Long-term fear conditioning training was affected in rats but there was no effect in short term conditioning. Specifically, amygdala fear conditioning was lost. This is a type of trace conditioning which is a form of learning that requires association of a conditioned stimulus with an unconditioned stimulus. This effect was lost in PI3K knockdowns and increased in PI3K overexpressions.<ref name = "Sui_2008" />
== Role in brain growth ==
In addition to its role in synaptic plasticity described above, PI3K-AKT signaling pathway also has an important role in brain growth, which is altered when PI3K signaling is disturbed. For example, intracranial volume is also associated with this pathway, in particular with ''AKT3'' intronic variants.<ref>{{cite journal | vauthors = Adams HH, Hibar DP, Chouraki V, Stein JL, Nyquist PA, Rentería ME, etal | title = Novel genetic loci underlying human intracranial volume identified through genome-wide association | journal = Nature Neuroscience | volume = 19 | issue = 12 | pages = 1569–1582 | date = December 2016 | pmid = 27694991 | pmc = 5227112 | doi = 10.1038/nn.4398 }}</ref> [[Thyroid hormones|Thyroid hormone]] was originally identified as the primary regulator of brain growth and cognition, and recent evidence has demonstrated that thyroid hormone produces some of its effects on the maturation and plasticity of synapses through PI3K.<ref>{{cite journal | vauthors = Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, Williams JG, Stapleton HM, Gentile S, Armstrong DL | display-authors = 6 | title = A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo | journal = Endocrinology | volume = 155 | issue = 9 | pages = 3713–24 | date = September 2014 | pmid = 24932806 | pmc = 4138568 | doi = 10.1210/en.2013-2058 }}</ref>
== See also ==
* [[AKT inhibitor]]
* [[Akt/PKB signaling pathway]]
* [[mTOR inhibitor]]
* [[PI3K inhibitor]]
* [[PTEN (gene)|PTEN]]
== References ==
{{reflist|30em}}
{{Signal transduction}}
{{DEFAULTSORT:PI3K AKT mTOR pathway}}
[[Category:Signal transduction]]