Somatic Mutations of PIK3R1 Promote Gliomagenesis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Nov 21

PMID 23166678

Citations 40

Authors

Steven N Quayle

Jennifer Y Lee

Lydia W T Cheung

Li Ding

Ruprecht Wiedemeyer

Robert W Dewan

Emmet Huang-Hobbs

Li Zhuang

Richard K Wilson

Keith L Ligon

Gordon B Mills

Lewis C Cantley

Lynda Chin

Affiliations

Soon will be listed here.

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.

Citing Articles

Potential Diagnostic and Clinical Significance of Selected Genetic Alterations in Glioblastoma.

Tomoszkova S, Skarda J, Lipina R Int J Mol Sci. 2024; 25(8).

PMID: 38674026 PMC: 11050250. DOI: 10.3390/ijms25084438.

Biomolecules to Biomarkers? U87MG Marker Evaluation on the Path towards Glioblastoma Multiforme Pathogenesis.

Pokorna M, Kutna V, Ovsepian S, Matej R, Cerna M, OLeary V Pharmaceutics. 2024; 16(1).

PMID: 38258133 PMC: 10818292. DOI: 10.3390/pharmaceutics16010123.

Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers.

Cobleigh M, Layng K, Mauer E, Mahon B, Hockenberry A, Abukhdeir A Breast Cancer Res Treat. 2023; 204(2):407-414.

PMID: 38153569 DOI: 10.1007/s10549-023-07196-4.

Tumor radiogenomics in gliomas with Bayesian layered variable selection.

Mohammed S, Kurtek S, Bharath K, Rao A, Baladandayuthapani V Med Image Anal. 2023; 90:102964.

PMID: 37797481 PMC: 10653647. DOI: 10.1016/j.media.2023.102964.

GradWise: A Novel Application of a Rank-Based Weighted Hybrid Filter and Embedded Feature Selection Method for Glioma Grading with Clinical and Molecular Characteristics.

Tasci E, Jagasia S, Zhuge Y, Camphausen K, Krauze A Cancers (Basel). 2023; 15(18).

PMID: 37760597 PMC: 10526509. DOI: 10.3390/cancers15184628.

References

Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010; 9(7):1956-67. DOI: 10.1158/1535-7163.MCT-09-1012. 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

Kinross K, Montgomery K, Kleinschmidt M, Waring P, Ivetac I, Tikoo A . An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest. 2012; 122(2):553-7. PMC: 3266789. DOI: 10.1172/JCI59309. View

Knobbe C, Reifenberger G . Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol. 2003; 13(4):507-18. PMC: 8095764. DOI: 10.1111/j.1750-3639.2003.tb00481.x. View

Sonoda Y, Ozawa T, Hirose Y, Aldape K, McMahon M, Berger M . Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res. 2001; 61(13):4956-60. View

. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008; 455(7216):1061-8. PMC: 2671642. DOI: 10.1038/nature07385. View

Serunian L, Auger K, Cantley L . Identification and quantification of polyphosphoinositides produced in response to platelet-derived growth factor stimulation. Methods Enzymol. 1991; 198:78-87. DOI: 10.1016/0076-6879(91)98010-4. View

Steck P, Pershouse M, Jasser S, Yung W, Lin H, Ligon A . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15(4):356-62. DOI: 10.1038/ng0497-356. View

Holland E, Celestino J, Dai C, Schaefer L, Sawaya R, Fuller G . Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000; 25(1):55-7. DOI: 10.1038/75596. View

10.

Wood L, Parsons D, Jones S, Lin J, Sjoblom T, Leary R . The genomic landscapes of human breast and colorectal cancers. Science. 2007; 318(5853):1108-13. DOI: 10.1126/science.1145720. View

11.

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

12.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View

13.

Sonoda Y, Ozawa T, Aldape K, Deen D, Berger M, Pieper R . Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res. 2001; 61(18):6674-8. View

14.

Parsons D, Jones S, Zhang X, Cheng-Ho Lin J, Leary R, Angenendt P . An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321(5897):1807-12. PMC: 2820389. DOI: 10.1126/science.1164382. View

15.

Zheng H, Ying H, Yan H, Kimmelman A, Hiller D, Chen A . p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008; 455(7216):1129-33. PMC: 4051433. DOI: 10.1038/nature07443. View

16.

Kang S, Bader A, Vogt P . Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005; 102(3):802-7. PMC: 545580. DOI: 10.1073/pnas.0408864102. View

17.

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

18.

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

19.

Furnari F, Fenton T, Bachoo R, Mukasa A, Stommel J, Stegh A . Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007; 21(21):2683-710. DOI: 10.1101/gad.1596707. View

20.

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View