Role of PI3K/AKT/mTOR in Cancer Signaling

  • Nicci Owusu-Brackett
  • Maryam Shariati
  • Funda Meric-BernstamEmail author


Phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a crucial role in integrating a variety of extracellular stimuli to regulate growth and development. The pathway impacts diverse biological functions and is a prominent player in vital cellular processes such as growth and proliferation. PI3K/AKT/mTOR signaling has been implicated in the pathogenesis of various human cancers and is one of the most frequently deregulated pathways in cancer. Every major node of this signaling network is activated in a wide range of human tumors. Mechanisms for the pathway activation include activation of receptor tyrosine kinases (RTKs) upstream of PI3K, mutation or amplification of PIK3CA encoding p110α catalytic subunit of PI3K, mutation or loss of PTEN tumor suppressor gene, and mutation or amplification of AKT1. Once the pathway is activated, signaling through AKT can stimulate a series of substrates including mTOR which is involved in protein synthesis. The central role of the pathway in tumor cell biology has led to a sizeable ongoing effort in the development of pharmacological agents targeting different components of the pathway. Currently mTOR inhibitors are approved for several indications, and there are several novel PI3K/AKT/mTOR inhibitors in clinical trials, and some demonstrate promise for the treatment of hyperactivated PI3K tumors. A better understanding of the pathway oncogenic mechanisms, different ways in which the signaling network is upregulated, and properties of distinct PI3K/AKT/mTOR genetic alterations will guide future strategic approaches for rational combination therapies.


PI3K Tumorigenicity AKT1 PTEN mTOR signaling Targeted therapy Combinational therapy 


  1. 1.
    Vanhaesebroeck B, et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.CrossRefPubMedGoogle Scholar
  3. 3.
    Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–510.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19–65.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dey N, De P, Leyland-Jones B. PI3K-mTOR in cancer and cancer therapy. 2016. Humana Press/Springer, New York.Google Scholar
  7. 7.
    John Mendelsohn GM, Meric-Bernstam F. Personalized cancer therapy. Knowledge base for precision oncology. The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy University of Texas MD Anderson Cancer Center. 2015.
  8. 8.
    Juric D, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature. 2015;518(7538):240–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Meric-Bernstam F, et al. A decision support framework or genomically informed investigational cancer therapy. J Natl Cancer Inst. 2015;107(7):djv098.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wagle N, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 2014;371(15):1426–33.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Andre F, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Hassan B, et al. Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors. Oncotarget. 2014;5(18):8544–57.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicci Owusu-Brackett
    • 1
  • Maryam Shariati
    • 2
  • Funda Meric-Bernstam
    • 3
    • 4
    • 5
    Email author
  1. 1.Department of Surgical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Investigational Cancer Therapeutics, Graduate School of Biomedical SciencesThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer TherapyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.Department of Breast Surgical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations