PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

Key Points

  • Oncogenic mutation of the phosphatidylinositol 3-kinase (PI3K) catalytic isoform p110α is frequent in human cancers, whereas the catalytic isoforms p110β, p110δ and p110γ are rarely mutated but can be overexpressed. Mutation or loss of expression of regulatory isoform p85α is also associated with cancer.

  • Although class IA PI3K catalytic isoforms share structural and substrate similarities, they have specific roles in mediating PI3K signalling in different physiological and oncogenic contexts.

  • Cancer cells with upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations or activating p110α mutations are highly dependent on p110α, even in the presence of mutation or loss of PTEN.

  • In many cases, tumorigenesis that is driven by PTEN loss depends on p110β. However, PI3K isoform dependence in PTEN-deficient transformation may be governed by other PI3K isoforms that are dominant in a tissue or compartment, or shifted by coexisting oncogenic mutations.

  • Isoforms p110α, p110δ and p110γ bind to and are activated by RAS subfamily GTPases, while p110β binds to and is activated by RHO subfamily GTPases RAC1 and CDC42.

  • Non-isoform-selective pan-PI3K inhibitors have not yielded exciting clinical results, but second-generation PI3K drugs that target individual PI3K isoforms may be able to achieve greater therapeutic efficacy by offering improved specificity and reduced toxicity.

  • The p110δ-selective inhibitor idelalisib has been remarkably effective in clinical trials for patients with B cell malignancies, while p110α-selective inhibitors have shown promise in early-phase trials for patients with solid tumours with PIK3CA mutations or HER2 amplification.

  • Intrinsic and acquired resistance mechanisms are a continuing challenge for PI3K-directed therapeutic approaches. To overcome this, combination therapies and alternative dosing strategies are being developed and evaluated in both preclinical and clinical settings.

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic.

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Figure 1: The PI3K family comprises several classes and isoforms.
Figure 2: Signalling by class I, II and III PI3K isoforms.
Figure 3: Divergent roles of class I PI3K catalytic isoforms in different signalling contexts.
Figure 4: An overview of PI3K inhibitors and their combination with other therapeutics.

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Acknowledgements

The authors thank T. M. Roberts for critical reading of the manuscript, T. M. Roberts and L. C. Cantley for discussions, and N. Rosen and J. A. Engelman for sharing unpublished observations. They also thank the reviewers for their suggestions and apologize to the many colleagues whose work they were unable cite owing to space limitations. Research in the laboratory of J.J.Z. is supported by the US National Institutes of Health (NIH) grants CA172461-01, P50 CA168504-01A1, P50 CA165962-01A1 and the Stand Up to Cancer Dream Team Translational Research grant SU2C-AACR-DT0209.

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Correspondence to Jean J. Zhao.

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FURTHER INFORMATION

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Supplementary information

Supplementary information S1

Class I PI3K isoform alterations in cancer (PDF 357 kb)

Supplementary information S2

Genetically engineered mouse models of PI3K isoforms in cancer (PDF 286 kb)

Supplementary information S3

Combination of PI3K inhibitors with other targeted therapies in the clinic (PDF 399 kb)

Glossary

Myristoylated

Refers to an irreversible co-translational modification of proteins, in which a myristoyl group is covalently attached to an amino acid at the amino terminal of a nascent polypeptide, promoting membrane localization of the modified protein.

Congenital mosaic overgrowth syndromes

A clinically heterogeneous group of genetic disorders characterized by abnormal progressive localized growth. They are caused by diverse somatic mutations and are associated with increased cancer risk.

Inter-SRC homology 2 domain

(iSH2 domain). The domain of p85 regulatory phosphatidylinositol 3-kinase (PI3K) isoforms that is located between the carboxy- and amino-terminal SH2 domains and that directly interacts with class IA p110 catalytic isoforms.

Megalencephaly syndromes

A collection of sporadic overgrowth disorders characterized by enlarged brain size and other distinct features.

SH2 domains

Structurally conserved protein–protein interaction domains that facilitate interactions with phosphorylated tyrosine residues on other proteins.

RAS superfamily proteins

Small monomeric membrane-associated GTPases, which are divided into the RAS, RHO, RAB, ARF and RAN subfamilies based on structure and function.

RAS GTPases

A subfamily of RAS superfamily GTPases that have crucial roles in signal transduction.In mammals, the three major RAS subfamily members are HRAS, KRAS and NRAS.

RHO family GTPases

A subfamily of RAS superfamily proteins that share similar roles in signal transduction to RAS GTPases and are best characterized for their roles in the regulation of cell shape, movement and polarity.

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Thorpe, L., Yuzugullu, H. & Zhao, J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15, 7–24 (2015). https://doi.org/10.1038/nrc3860

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