The Structural Basis of PI3K Cancer Mutations: from Mechanism to Therapy

Overview

Journal Cancer Res

Specialty Oncology

Date 2014 Jan 25

PMID 24459181

Citations 28

Authors

Shujuan Liu

Stefan Knapp

Ahmed Ashour Ahmed

Affiliations

Soon will be listed here.

Abstract

While genetic alteration in the p85α-p110α (PI3K) complex represents one of the most frequent driver mutations in cancer, the wild-type complex is also required for driving cancer progression through mutations in related pathways. Understanding the mechanistic basis of the function of the phosphoinositide 3-kinase (PI3K) is essential for designing optimal therapeutic targeting strategies. Recent structural data of the p85α/p110α complex unraveled key insights into the molecular mechanisms of the activation of the complex and provided plausible explanations for the well-established biochemical data on p85/p110 dimer regulation. A wealth of biochemical and biologic information supported by recent genetic findings provides a strong basis for additional p110-independent function of p85α in the regulation of cell survival. In this article, we review the structural, biochemical, and biologic mechanisms through which p85α regulates the cancer cell life cycle with an emphasis on the recently discovered genetic alterations in cancer. As cancer progression is dependent on multiple biologic processes, targeting key drivers such as the PI3K may be required for efficacious therapy of heterogeneous tumors typically present in patients with late-stage disease.

Citing Articles

Molecular Basis of Oncogenic PI3K Proteins.

Sheng Z, Beck P, Gabby M, Habte-Mariam S, Mitkos K Cancers (Basel). 2025; 17(1).

PMID: 39796708 PMC: 11720314. DOI: 10.3390/cancers17010077.

Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.

Li H, Wen X, Ren Y, Fan Z, Zhang J, He G Mol Cancer. 2024; 23(1):164.

PMID: 39127670 PMC: 11316348. DOI: 10.1186/s12943-024-02072-1.

A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism.

Thapa N, Chen M, Cryns V, Anderson R Cell Rep. 2024; 43(5):114119.

PMID: 38630589 PMC: 11380499. DOI: 10.1016/j.celrep.2024.114119.

Emerging role of extracellular vesicles and exogenous stimuli in molecular mechanisms of peripheral nerve regeneration.

Izhiman Y, Esfandiari L Front Cell Neurosci. 2024; 18:1368630.

PMID: 38572074 PMC: 10989355. DOI: 10.3389/fncel.2024.1368630.

Structural and Dynamic Analyses of Pathogenic Variants in Reveal a Shared Mechanism Associated among Cancer, Undergrowth, and Overgrowth Syndromes.

Dsouza N, Cottrell C, Davies O, Tollefson M, Frieden I, Basel D Life (Basel). 2024; 14(3).

PMID: 38541623 PMC: 10971029. DOI: 10.3390/life14030297.

References

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

Fu Z, Aronoff-Spencer E, Backer J, Gerfen G . The structure of the inter-SH2 domain of class IA phosphoinositide 3-kinase determined by site-directed spin labeling EPR and homology modeling. Proc Natl Acad Sci U S A. 2003; 100(6):3275-80. PMC: 152282. DOI: 10.1073/pnas.0535975100. View

Cheung L, Hennessy B, Li J, Yu S, Myers A, Djordjevic B . High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011; 1(2):170-85. PMC: 3187555. DOI: 10.1158/2159-8290.CD-11-0039. View

Vadas O, Burke J, Zhang X, Berndt A, Williams R . Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal. 2011; 4(195):re2. DOI: 10.1126/scisignal.2002165. View

Huang C, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu V, Kinzler K . The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007; 318(5857):1744-8. DOI: 10.1126/science.1150799. View

Jimenez C, Portela R, Mellado M, Rodriguez-Frade J, Collard J, Serrano A . Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J Cell Biol. 2000; 151(2):249-62. PMC: 2192656. DOI: 10.1083/jcb.151.2.249. View

Urick M, Rudd M, Godwin A, Sgroi D, Merino M, Bell D . PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011; 71(12):4061-7. PMC: 3117071. DOI: 10.1158/0008-5472.CAN-11-0549. View

Bader A, Kang S, Vogt P . Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A. 2006; 103(5):1475-9. PMC: 1360603. DOI: 10.1073/pnas.0510857103. View

Songyang Z, Shoelson S, Chaudhuri M, Gish G, Pawson T, Haser W . SH2 domains recognize specific phosphopeptide sequences. Cell. 1993; 72(5):767-78. DOI: 10.1016/0092-8674(93)90404-e. View

10.

Whitman M, Downes C, Keeler M, Keller T, Cantley L . Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988; 332(6165):644-6. DOI: 10.1038/332644a0. View

11.

Rudd M, Price J, Fogoros S, Godwin A, Sgroi D, Merino M . A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res. 2011; 17(6):1331-40. PMC: 3060282. DOI: 10.1158/1078-0432.CCR-10-0540. View

12.

Sun M, Hillmann P, Hofmann B, Hart J, Vogt P . Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha. Proc Natl Acad Sci U S A. 2010; 107(35):15547-52. PMC: 2932613. DOI: 10.1073/pnas.1009652107. View

13.

Garcia Z, Silio V, Marques M, Cortes I, Kumar A, Hernandez C . A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis. EMBO J. 2006; 25(20):4740-51. PMC: 1618105. DOI: 10.1038/sj.emboj.7601324. View

14.

Santos S, Lacronique V, Bouchaert I, Monni R, Bernard O, Gisselbrecht S . Constitutively active STAT5 variants induce growth and survival of hematopoietic cells through a PI 3-kinase/Akt dependent pathway. Oncogene. 2001; 20(17):2080-90. DOI: 10.1038/sj.onc.1204308. View

15.

Jaiswal B, Janakiraman V, Kljavin N, Chaudhuri S, Stern H, Wang W . Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell. 2009; 16(6):463-74. PMC: 2804903. DOI: 10.1016/j.ccr.2009.10.016. View

16.

. Comprehensive molecular portraits of human breast tumours. Nature. 2012; 490(7418):61-70. PMC: 3465532. DOI: 10.1038/nature11412. View

17.

Mandelker D, Gabelli S, Schmidt-Kittler O, Zhu J, Cheong I, Huang C . A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009; 106(40):16996-7001. PMC: 2761334. DOI: 10.1073/pnas.0908444106. View

18.

Carpenter C, Auger K, Chanudhuri M, Yoakim M, Schaffhausen B, Shoelson S . Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem. 1993; 268(13):9478-83. View

19.

Whitman M, Kaplan D, Schaffhausen B, Cantley L, Roberts T . Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature. 1985; 315(6016):239-42. DOI: 10.1038/315239a0. View

20.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S . High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304(5670):554. DOI: 10.1126/science.1096502. View