PI3K and Cancer: Lessons, Challenges and Opportunities

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2014 Feb 1

PMID 24481312

Citations 852

Authors

David A Fruman

Christian Rommel

Affiliations

Soon will be listed here.

Abstract

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

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References

Lim S, Saw T, Zhang M, Janes M, Nacro K, Hill J . Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A. 2013; 110(25):E2298-307. PMC: 3690864. DOI: 10.1073/pnas.1301838110. View

Wu H, Shekar S, Flinn R, El-Sibai M, Jaiswal B, Sen K . Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proc Natl Acad Sci U S A. 2009; 106(48):20258-63. PMC: 2787125. DOI: 10.1073/pnas.0902369106. View

Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim J . Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010; 70(2):621-31. DOI: 10.1158/0008-5472.CAN-09-2340. 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

Guo F, Li J, Du W, Zhang S, OConnor M, Thomas G . mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells. Leukemia. 2013; 27(10):2040-2046. PMC: 4225699. DOI: 10.1038/leu.2013.93. View

Hoellenriegel J, Meadows S, Sivina M, Wierda W, Kantarjian H, Keating M . The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011; 118(13):3603-12. PMC: 4916562. DOI: 10.1182/blood-2011-05-352492. View

Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013; 340(6136):1100-6. PMC: 3728654. DOI: 10.1126/science.1232044. View

Blanco-Aparicio C, Collazo A, Oyarzabal J, Leal J, Albaran M, Lima F . Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition. Cancer Lett. 2010; 300(2):145-53. DOI: 10.1016/j.canlet.2010.09.016. View

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

10.

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

11.

Janes M, Fruman D . Targeting TOR dependence in cancer. Oncotarget. 2010; 1(1):69-76. PMC: 2908250. DOI: 10.18632/oncotarget.110. View

12.

Subramaniam P, Whye D, Efimenko E, Chen J, Tosello V, De Keersmaecker K . Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell. 2012; 21(4):459-72. DOI: 10.1016/j.ccr.2012.02.029. View

13.

Fruman D . Towards an understanding of isoform specificity in phosphoinositide 3-kinase signalling in lymphocytes. Biochem Soc Trans. 2004; 32(Pt 2):315-9. DOI: 10.1042/bst0320315. View

14.

Liu N, Rowley B, Bull C, Schneider C, Haegebarth A, Schatz C . BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013; 12(11):2319-30. DOI: 10.1158/1535-7163.MCT-12-0993-T. View

15.

Vanneman M, Dranoff G . Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012; 12(4):237-51. PMC: 3967236. DOI: 10.1038/nrc3237. View

16.

Konicek B, Stephens J, McNulty A, Robichaud N, Peery R, Dumstorf C . Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. Cancer Res. 2011; 71(5):1849-57. DOI: 10.1158/0008-5472.CAN-10-3298. View

17.

Yang J, Wang J, Chen K, Guo G, Xi R, Rothman P . eIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes. Cancer Res. 2013; 73(15):4898-908. DOI: 10.1158/0008-5472.CAN-12-4277. View

18.

Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A . An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity. 2010; 33(6):929-41. PMC: 3133602. DOI: 10.1016/j.immuni.2010.11.024. View

19.

Lemmon M . Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol. 2008; 9(2):99-111. DOI: 10.1038/nrm2328. View

20.

Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002; 2(3):183-92. DOI: 10.1016/s1535-6108(02)00127-7. View