The PI3K Pathway in Human Disease

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Aug 13

PMID 28802037

Citations 1159

Authors

David A Fruman

Honyin Chiu

Benjamin D Hopkins

Shubha Bagrodia

Lewis C Cantley

Robert T Abraham

Affiliations

Soon will be listed here.

Abstract

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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References

Loconte D, Grossi V, Bozzao C, Forte G, Bagnulo R, Stella A . Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors. PLoS One. 2015; 10(4):e0123092. PMC: 4411002. DOI: 10.1371/journal.pone.0123092. View

Weichhart T, Hengstschlager M, Linke M . Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015; 15(10):599-614. PMC: 6095456. DOI: 10.1038/nri3901. View

Rolf J, Bell S, Kovesdi D, Janas M, Soond D, Webb L . Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J Immunol. 2010; 185(7):4042-52. DOI: 10.4049/jimmunol.1001730. View

Brown K, Toker A . The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Rep. 2015; 7:13. PMC: 4335789. DOI: 10.12703/P7-13. View

Andre F, Hurvitz S, Fasolo A, Tseng L, Jerusalem G, Wilks S . Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3. J Clin Oncol. 2016; 34(18):2115-24. DOI: 10.1200/JCO.2015.63.9161. View

Dominguez-Sola D, Kung J, Holmes A, Wells V, Mo T, Basso K . The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program. Immunity. 2015; 43(6):1064-74. DOI: 10.1016/j.immuni.2015.10.015. View

Coutre S, Barrientos J, Brown J, de Vos S, Furman R, Keating M . Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015; 56(10):2779-86. PMC: 4732460. DOI: 10.3109/10428194.2015.1022770. View

Pai C, Walsh C, Fruman D . Context-Specific Function of S6K2 in Th Cell Differentiation. J Immunol. 2016; 197(8):3049-3058. PMC: 5101169. DOI: 10.4049/jimmunol.1600167. View

Schmid M, Avraamides C, Dippold H, Franco I, Foubert P, Ellies L . Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011; 19(6):715-27. PMC: 3144144. DOI: 10.1016/j.ccr.2011.04.016. View

10.

Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y . PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ. Cell Rep. 2012; 1(4):360-73. DOI: 10.1016/j.celrep.2012.02.007. View

11.

Ramadani F, Bolland D, Garcon F, Emery J, Vanhaesebroeck B, Corcoran A . The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal. 2010; 3(134):ra60. PMC: 3540743. DOI: 10.1126/scisignal.2001104. View

12.

Juric D, de Bono J, LoRusso P, Nemunaitis J, Heath E, Kwak E . A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies. Clin Cancer Res. 2017; 23(17):5015-5023. PMC: 6858996. DOI: 10.1158/1078-0432.CCR-16-2888. View

13.

Thorpe L, Yuzugullu H, Zhao J . PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2014; 15(1):7-24. PMC: 4384662. DOI: 10.1038/nrc3860. View

14.

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

15.

Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung S . SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006; 127(1):125-37. DOI: 10.1016/j.cell.2006.08.033. View

16.

Linke M, Pham H, Katholnig K, Schnoller T, Miller A, Demel F . Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat Immunol. 2017; 18(3):293-302. PMC: 5321578. DOI: 10.1038/ni.3655. View

17.

Dengler H, Baracho G, Omori S, Bruckner S, Arden K, Castrillon D . Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol. 2008; 9(12):1388-98. PMC: 2679692. DOI: 10.1038/ni.1667. View

18.

Limon J, Fruman D . Akt and mTOR in B Cell Activation and Differentiation. Front Immunol. 2012; 3:228. PMC: 3412259. DOI: 10.3389/fimmu.2012.00228. View

19.

Guichard S, Curwen J, Bihani T, DCruz C, Yates J, Grondine M . AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules. Mol Cancer Ther. 2015; 14(11):2508-18. DOI: 10.1158/1535-7163.MCT-15-0365. View

20.

Cardnell R, Feng Y, Mukherjee S, Diao L, Tong P, Stewart C . Activation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer. PLoS One. 2016; 11(4):e0152584. PMC: 4824499. DOI: 10.1371/journal.pone.0152584. View