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Understanding the PI3K/AKT pathway

PI3K - AKT pathway

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

A crucial pathway influencing diverse cellular functions1

The PI3K/AKT signaling pathway is a key regulator of normal cellular processes involved in cell growth, proliferation, metabolism, motility, survival, and apoptosis. Aberrant activation of the PI3K/AKT pathway promotes the survival and proliferation of tumor cells in many human cancers.1,2

Key molecules involved in this signaling pathway

Phosphatidylinositol 3-kinase (PI3K), AKT, a serine/threonine protein kinase also known as protein kinase B (PKB), and mammalian target of rapamycin (mTOR) are 3 major nodes in the pathway. They are typically activated by upstream signaling of tyrosine kinases and other receptor molecules such as hormones and mitogenic factors.3

There are 3 classes of PI3Ks, with Class I being widely implicated in cancer.4 Class I PI3Ks are activated by receptor tyrosine kinases (RTKs) or G protein–coupled receptors (GPCRs), and their primary role is to convert phosphatidylinositol 4,5-bisphosphate (PI4,5P2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). AKT, the central node of the pathway, is activated following recruitment to the plasma membrane by PIP3. It acts downstream of PI3K to regulate cellular processes, including cell survival, proliferation, and growth.5,6 mTOR is a key protein in the pathway that acts both upstream and downstream of AKT.7,8 mTOR is active in 2 different multiprotein complexes, target of rapamycin complex (TORC) 1 and TORC2, and it regulates the protein synthesis necessary for cell growth, proliferation, angiogenesis, and other cellular endpoints.7,9

PI3K/AKT pathway and cancer

Aberrant PI3K/AKT activation promotes tumor progression and resistance to treatment10

The PI3K/AKT signaling pathway regulates cell survival and proliferation.11 Aberrant activation of the pathway is commonly observed in many human cancers, including breast, lung, ovarian, and prostate.4,6,8,10

Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies.8,10 The activation of the PI3K/AKT pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types.12

Chemotherapeutic agents can modulate activity of the PI3K/AKT pathway, which contributes to the development of acquired resistance.2

Aberrant activation can result from molecular alterations of the pathway's key components.10 Alterations in PI3K, AKT, or mTOR can induce cell line transformation and tumor formation in transgenic mice.13 Preclinical knockout of PI3K blocked oncogenic transformation.4 Knockout or suppression of AKT or mTOR has inhibited tumor growth and invasiveness in animal models.14,15

PI3K plays a role in cell signaling and membrane trafficking16

PI3K in cell signaling and membrane trafficking

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

Each of the 3 classes of phosphatidylinositol 3-kinases (PI3Ks) has its own substrate specificity, tissue distribution, and mechanism of action.17,18 Class I PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PI4,5P2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which mediates AKT activation.5

Class I PI3Ks, which are present in all cell types, are comprised of 4 isoforms: p110α, p110β, p110δ, and p110γ.16,19 Although the 4 isoforms serve distinct functions based on cellular context (eg, p110δ and p110γ are mainly restricted to function in leukocytes), their activation leads to the production of PIP3, which mediates AKT activation through membrane recruitment by binding to its pleckstrin homology (PH) domain.5,16

Somatic mutations in p110α have been identified in a variety of cancer types.17 These mutations increase kinase activity and contribute to transformation.20 Mutations in phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA), the gene coding for p110α, are prevalent in a diverse variety of cancer types, making PIK3CA the most commonly mutated oncogene.20

Cancer types with a high prevalence of PIK3CA mutation include liver, breast, and colorectal.21 The PI3K signaling pathway is altered in the majority of patients with advanced-stage prostate cancer, with biallelic loss of the tumor suppressor phosphatase and tensin homolog (PTEN) being the most common somatic mutation.14

PI3K inhibition may block the growth of tumors activated by oncogenic receptor tyrosine kinases (RTKs), PI3K mutants, and/or PTEN loss of function. Inhibition strategies include adenosine triphosphate (ATP)-competitive pan-PI3K selective inhibitors, isoform-specific PI3K inhibitors, and inhibitors targeting isoform-specific PI3K mutations.13,20

PTEN controls AKT signaling and serves as a tumor suppressor22

Enlarged PTEN

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

Phosphatase and tensin homolog (PTEN) acts as a negative regulator of the PI3K/AKT pathway through its ability to convert phosphatidylinositol 3,4,5-trisphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PI4,5P2).5,22 Inactivating mutations or loss of heterozygosity in PTEN can lead to the hyperactivation of AKT signaling and increase the risk of cancer development.5

Germline mutations in PTEN have been described in a number of syndromes collectively known as PTEN hamartoma tumor syndrome (PHTS).22 Patients with PHTS have an increased incidence of breast, thyroid, and endometrial cancers, and PTEN is among the most commonly mutated tumor-suppressor genes in sporadic cancer. It has also been implicated in the development of multiple cancer types, including prostate, breast, endometrium, thyroid, central nervous system, lung, pancreas, liver, and adrenal glands. Additionally, it has been involved in cases of melanoma, leukemia, and lymphoma.22

AKT signaling is crucial in cellular processes and often dysregulated in many cancers5,23

Enlarged AKT

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

AKT is the central node of the PI3K/AKT pathway and has an essential regulatory role in multiple cellular processes.23,24 There are 3 highly homologous AKT isoforms (AKT 1, AKT 2, and AKT 3) that are encoded by separate genes and share over 80% amino acid sequence identity in mammalian cells.25

AKT is one of the most frequently activated protein kinases in human cancers. Hyperactivation of AKT may induce cell growth, lead to cell proliferation, and contribute toward resistance to apoptosis.25

In cancer, AKT activity is frequently elevated due to oncogenic growth factors, angiogenic factors, cytokines, and genetic alterations, including mutations and/or amplifications of the AKT1, AKT2, and AKT3 genes; loss of function of the phosphatase and tensin homolog (PTEN) tumor-suppressor; and mutations of the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) gene.15 Inactivation of PTEN and missense alleles of PIK3CA have been associated with constitutive activation of AKT. AKT activation has been correlated with various clinicopathologic parameters such as advanced disease and/or poor prognosis in a number of tumors.26

The oncogenic potential of the AKT pathway is further supported by the fact that a murine model-based conditional PTEN deletion, leading to increased activation of AKT signaling, may result in the development of metastatic cancer.14 Ectopic expression of constitutively active AKT resulted in oncogenic transformation, both in vitro and in vivo. In addition, downregulation or knockdown of AKT by antisense or small interfering ribonucleic acid (siRNA) significantly reduced tumor growth and invasiveness, as well as induced apoptosis and cell growth arrest only in tumor cells overexpressing AKT.15

PI3K/AKT Upregulation

Preclinical data suggest that the PI3K/AKT pathway may be upregulated as a result of targeting other signaling pathways.12,14,27

  • The PI3K/AKT pathway has been implicated as a key player in the development of resistance to endocrine therapy12
  • The activation of the PI3K/AKT pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types12
  • Repression of the androgen receptor in prostate cancer was shown in preclinical models to induce AKT activity, indicating the existence of a reciprocal feedback mechanism14,27
  • It has been reported that many tumors upregulate AKT in order to acquire resistance to standard chemotherapies and targeted therapies2
  • Inhibition of mammalian target of rapamycin complex (mTORC) 1 resulted in the upregulation of the AKT pathway, indicating the existence of a feedback loop28

Approaches that include targeting the PI3K/AKT pathway in combination with other treatment modalities may be viable strategies to address resistance mechanisms.12,14,27

    • Porta C, Paglino C, Mosca A. Front Oncol. 2014;4:64. PMID: 24782981

      Porta C, Paglino C, Mosca A. Front Oncol. 2014;4:64. PMID: 24782981

    • Huang WC, Hung MC. J Formos Med Assoc. 2009;108:180-194. PMID: 19293033

      Huang WC, Hung MC. J Formos Med Assoc. 2009;108:180-194. PMID: 19293033

    • Ruggero D, Sonenberg N. Oncogene. 2005;24:7426-7434. PMID: 16288289

      Ruggero D, Sonenberg N. Oncogene. 2005;24:7426-7434. PMID: 16288289

    • Liu P, Cheng H, Roberts TM, Zhao JJ. Nat Rev Drug Discov. 2009;8:627-644. PMID: 19644473

      Liu P, Cheng H, Roberts TM, Zhao JJ. Nat Rev Drug Discov. 2009;8:627-644. PMID: 19644473

    • Manning BD, Toker A. Cell. 2017;169:381-405. PMID: 28431241

      Manning BD, Toker A. Cell. 2017;169:381-405. PMID: 28431241

    • Myers AP, Cantley LC. Sci Transl Med. 2010;2:48ps45. PMID: 20826838

      Myers AP, Cantley LC. Sci Transl Med. 2010;2:48ps45. PMID: 20826838

    • Slomovitz BM, Coleman RL. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003

      Slomovitz BM, Coleman RL. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003

    • Morgan TM, Koreckij TD, Corey E. Curr Cancer Drug Targets. 2009;9:237-249. PMID: 19275762

      Morgan TM, Koreckij TD, Corey E. Curr Cancer Drug Targets. 2009;9:237-249. PMID: 19275762

    • Hung CM, Garcia-Haro L, Sparks CA, Guertin DA. Cold Spring Harb Perspect Biol. 2012;4:a008771. PMID: 23124837

      Hung CM, Garcia-Haro L, Sparks CA, Guertin DA. Cold Spring Harb Perspect Biol. 2012;4:a008771. PMID: 23124837

    • Sarris EG, Saif MW, Syrigos KN. Pharmaceuticals. 2012;5:1236-1264. PMID: 24281308

      Sarris EG, Saif MW, Syrigos KN. Pharmaceuticals. 2012;5:1236-1264. PMID: 24281308

    • Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Biochem Pharmacol. 2014;90:197-207. PMID: 24863259

      Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Biochem Pharmacol. 2014;90:197-207. PMID: 24863259

    • LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407

      LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407

    • Rodon J, Dienstmann R, Serra V, Tabernero J. Nat Rev Clin Oncol. 2013;10:143-153. PMID: 23400000

      Rodon J, Dienstmann R, Serra V, Tabernero J. Nat Rev Clin Oncol. 2013;10:143-153. PMID: 23400000

    • Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005

      Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005

    • Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. Oncogene. 2005;24:7482-7492. PMID: 16288295

      Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. Oncogene. 2005;24:7482-7492. PMID: 16288295

    • Jean S, Kiger AA. J Cell Sci. 2014;127:923-928. PMID: 24587488

      Jean S, Kiger AA. J Cell Sci. 2014;127:923-928. PMID: 24587488

    • Thorpe LM, Yuzugullu H, Zhao JJ. Nat Rev Cancer. 2015;15:7-24. PMID: 25533673

      Thorpe LM, Yuzugullu H, Zhao JJ. Nat Rev Cancer. 2015;15:7-24. PMID: 25533673

    • Cantrell DA. J Cell Sci. 2001;114:1439-1445. PMID: 11282020

      Cantrell DA. J Cell Sci. 2001;114:1439-1445. PMID: 11282020

    • Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B. Proc Natl Acad Sci U S A. 2010;107:11381-11386. PMID: 20534549

      Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B. Proc Natl Acad Sci U S A. 2010;107:11381-11386. PMID: 20534549

    • Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Biochim Biophys Acta. 2010;1804:533-540. PMID: 19962457

      Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Biochim Biophys Acta. 2010;1804:533-540. PMID: 19962457

    • National Cancer Institute. GDC data portal. https://portal.gdc.cancer.gov/genes/ENSG00000121879. Data released January 16, 2020. Accessed February 14, 2020.

      National Cancer Institute. GDC data portal. https://portal.gdc.cancer.gov/genes/ENSG00000121879. Data released January 16, 2020. Accessed February 14, 2020.

    • Hollander MC, Blumenthal GM, Dennis PA. Nat Rev Cancer. 2011;11:289-301. PMID: 21430697

      Hollander MC, Blumenthal GM, Dennis PA. Nat Rev Cancer. 2011;11:289-301. PMID: 21430697

    • Testa JR, Tsichlis PN. Oncogene. 2005;24:7391-7393. PMID: 16288285

      Testa JR, Tsichlis PN. Oncogene. 2005;24:7391-7393. PMID: 16288285

    • Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Oncogene. 2007;26:1932-1940. PMID: 17001314

      Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Oncogene. 2007;26:1932-1940. PMID: 17001314

    • Hay N. Cancer Cell. 2005;8:179-183. PMID: 16169463

      Hay N. Cancer Cell. 2005;8:179-183. PMID: 16169463

    • Altomare DA, Testa JR. Oncogene. 2005;24:7455-7464. PMID: 16288292

      Altomare DA, Testa JR. Oncogene. 2005;24:7455-7464. PMID: 16288292

    • Bitting RL, Armstrong AJ. Endocr Relat Cancer. 2013;20:R83-R99. PMID: 23456430

      Bitting RL, Armstrong AJ. Endocr Relat Cancer. 2013;20:R83-R99. PMID: 23456430

    • Gupta M, Hendrickson AEW, Yun SS, et al. Blood. 2012;119:476-487. PMID: 22080480

      Gupta M, Hendrickson AEW, Yun SS, et al. Blood. 2012;119:476-487. PMID: 22080480

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