PIK3CA mutations in human solid tumors: Role in sensitivity to various therapeutic approaches

Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival and motility. The PI3K pathway is considered to play an important role in tumorigenesis. Activating mutations of the p110α subunit of PI3K (PIK3CA) have been identified in a broad spectrum of tumors. Analyses of PIK3CA mutations reveals that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we analyze the contribution of the PIK3CA mutations in cancer, and their possible implications for diagnosis and therapy.

[1]  C. Hudis Trastuzumab--mechanism of action and use in clinical practice. , 2007, The New England journal of medicine.

[2]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[3]  Bert Vogelstein,et al.  The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations , 2007, Science.

[4]  J. Inazawa,et al.  PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma , 2006, Cancer science.

[5]  Amit Kumar,et al.  New Functions for PI3K in the Control of Cell Division , 2007, Cell cycle.

[6]  G. Thomas,et al.  Ribosomal S6 kinase signaling and the control of translation. , 1999, Experimental cell research.

[7]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[8]  Yuval Inbar,et al.  Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit , 2007, Science.

[9]  A. Toker,et al.  Akt/PKB Signaling in Cancer: A Function in Cell Motility and Invasion , 2006, Cell cycle.

[10]  Wayne A. Phillips,et al.  Mutation of the PIK3CA Gene in Ovarian and Breast Cancer , 2004, Cancer Research.

[11]  R. Weinberg,et al.  How cancer arises. , 1996, Scientific American.

[12]  Lyndsay N Harris,et al.  Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Hirano,et al.  The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity. , 1994, Molecular and cellular biology.

[14]  B. Hemmings,et al.  PKB Binding Proteins Getting in on the Akt , 2002, Cell.

[15]  R. McLendon,et al.  Mutations of PIK3CA in Anaplastic Oligodendrogliomas, High-Grade Astrocytomas, and Medulloblastomas , 2004, Cancer Research.

[16]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[17]  Francisca Vazquez,et al.  Regulation of PTEN Function as a PIP3 Gatekeeper Through Membrane Interaction , 2006, Cell cycle.

[18]  A. Gingras,et al.  The mRNA 5' cap-binding protein eIF4E and control of cell growth. , 1998, Current opinion in cell biology.

[19]  R. Parsons,et al.  PTEN: life as a tumor suppressor. , 2001, Experimental cell research.

[20]  Spiros Manolidis,et al.  PIK3CA Mutations in Head and Neck Squamous Cell Carcinoma , 2006, Clinical Cancer Research.

[21]  M. Kasuga,et al.  PI 3‐kinase: structural and functional analysis of intersubunit interactions. , 1994, The EMBO journal.

[22]  P. Vogt,et al.  A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  K. Liang,et al.  Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells , 2003, British Journal of Cancer.

[24]  Frank McCormick,et al.  High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. , 2005, Cancer research.

[25]  G. Hortobagyi,et al.  PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer , 2008, Breast Cancer Research.

[26]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[27]  W. Hohenberger,et al.  PIK3CA, KRAS, and BRAF mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/C) of the pancreas , 2008, Langenbeck's Archives of Surgery.

[28]  C. Downes,et al.  PTEN function: how normal cells control it and tumour cells lose it. , 2004, The Biochemical journal.

[29]  Sanjay Goel,et al.  PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. , 2008, Cancer research.

[30]  A. Lash,et al.  Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers , 2005, Clinical Cancer Research.

[31]  M. Czech,et al.  Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. , 1998, Trends in cell biology.

[32]  Jiayuh Lin,et al.  Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. , 2000, Anticancer research.

[33]  P. Vogt,et al.  Cancer-specific mutations in PIK3CA are oncogenic in vivo , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Waterfield,et al.  Signaling by distinct classes of phosphoinositide 3-kinases. , 1999, Experimental cell research.

[36]  J. Backer,et al.  Regulation of the p85/p110alpha phosphatidylinositol 3'-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains. , 1998, The Journal of biological chemistry.

[37]  Ming Tan,et al.  PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. , 2004, Cancer cell.

[38]  G. Mills,et al.  HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells , 2003, Oncogene.