Genomic complexity and AKT dependence in serous ovarian cancer.

UNLABELLED Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor. SIGNIFICANCE A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease.

[1]  G. Ning,et al.  The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. , 2011, The Journal of clinical endocrinology and metabolism.

[2]  R. Drapkin,et al.  New insights into the pathogenesis of serous ovarian cancer and its clinical impact. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  W. Weichert,et al.  Specific inhibition of AKT2 by RNA interference results in reduction of ovarian cancer cell proliferation: increased expression of AKT in advanced ovarian cancer. , 2007, Cancer letters.

[4]  S. Staal.  Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. Marchetti,et al.  AKT1E17K in human solid tumours , 2008, Oncogene.

[6]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[7]  Hans E. Huber,et al.  Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling , 2008, PloS one.

[8]  Gordon B Mills,et al.  Personalizing therapy for ovarian cancer: BRCAness and beyond. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Domenico Coppola,et al.  Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer , 2000, Oncogene.

[10]  J. Smyth,et al.  Characterization and properties of nine human ovarian adenocarcinoma cell lines. , 1988, Cancer research.

[11]  Richard Lugg,et al.  Mutation analysis of 24 known cancer genes in the NCI-60 cell line set , 2006, Molecular Cancer Therapeutics.

[12]  M. Hung,et al.  Aberrant expression of the c-erbB-2/neu protooncogene in ovarian cancer. , 1992, Cancer letters.

[13]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[14]  P. Leung,et al.  Ovarian surface epithelium: biology, endocrinology, and pathology. , 2001, Endocrine reviews.

[15]  G. Mills,et al.  Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells , 2006, Molecular Cancer Therapeutics.

[16]  Andrew K Godwin,et al.  AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth , 2004, Oncogene.

[17]  J. Sebolt-Leopold,et al.  Targeting the mitogen-activated protein kinase cascade to treat cancer , 2004, Nature Reviews Cancer.

[18]  G. Mills,et al.  A novel AKT3 mutation in melanoma tumours and cell lines , 2008, British Journal of Cancer.

[19]  Kathleen Haskell,et al.  Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model. , 2008, Bioorganic & medicinal chemistry letters.

[20]  Michael Peyton,et al.  Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo , 2010, PloS one.

[21]  C. Wolf,et al.  Cellular heterogeneity and drug resistance in two ovarian adenocarcinoma cell lines derived from a single patient , 1987, International journal of cancer.

[22]  Q. She,et al.  4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. , 2010, Cancer cell.

[23]  J. Warmus,et al.  The Discovery of the Benzhydroxamate MEK Inhibitors CI‐1040 and PD 0325901. , 2009 .

[24]  David D. L. Bowtell,et al.  The genesis and evolution of high-grade serous ovarian cancer , 2010, Nature Reviews Cancer.

[25]  S. Orsulic,et al.  Ovarian Cancer , 1993, British Journal of Cancer.

[26]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[27]  J. Sebolt-Leopold,et al.  Mechanisms of drug inhibition of signalling molecules , 2006, Nature.

[28]  R. Pearson,et al.  A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition. , 2006, Cancer research.

[29]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[30]  Anil K Sood,et al.  Early events in the pathogenesis of epithelial ovarian cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  C. Hoffmann,et al.  Flow cytometric analysis of G1- and G2/M-phase subpopulations in mammalian cell nuclei using side scatter and DNA content measurements. , 1990, Cytometry.

[32]  E. S. Venkatraman,et al.  A faster circular binary segmentation algorithm for the analysis of array CGH data , 2007, Bioinform..

[33]  J. Warmus,et al.  Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition , 2004, Nature Structural &Molecular Biology.

[34]  Barry S Taylor,et al.  Genomic and biological characterization of exon 4 KRAS mutations in human cancer. , 2010, Cancer research.

[35]  J. Mesirov,et al.  Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer , 2011, Proceedings of the National Academy of Sciences.

[36]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[37]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[38]  M. Wells,et al.  Precursor lesions of ovarian epithelial malignancy , 2001, Histopathology.

[39]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[40]  G. Ning,et al.  The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. , 2011, The Journal of clinical endocrinology and metabolism.

[41]  Jie Zhou,et al.  Akt1 governs breast cancer progression in vivo , 2007, Proceedings of the National Academy of Sciences.

[42]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[43]  S. Chandarlapaty,et al.  Protocol for PTEN Expression by Immunohistochemistry in Formalin-fixed Paraffin-embedded Human Breast Carcinoma , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[44]  B. Vanhaesebroeck,et al.  The emerging mechanisms of isoform-specific PI3K signalling , 2010, Nature Reviews Molecular Cell Biology.

[45]  Sarat Chandarlapaty,et al.  AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. , 2011, Cancer cell.

[46]  A. Tolcher,et al.  A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  H. Varmus,et al.  Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. , 2002, Cancer cell.

[48]  D. Coppola,et al.  Combination of Farnesyltransferase and Akt Inhibitors Is Synergistic in Breast Cancer Cells and Causes Significant Breast Tumor Regression in ErbB2 Transgenic Mice , 2011, Clinical Cancer Research.

[49]  William Pao,et al.  Genetic predictors of MEK dependence in non-small cell lung cancer. , 2008, Cancer research.

[50]  F. McCormick,et al.  Mutation Analysis of BRAF, MEK1 and MEK2 in 15 Ovarian Cancer Cell Lines: Implications for Therapy , 2007, PloS one.

[51]  R. Pearson,et al.  A Specific Role for AKT 3 in the Genesis of Ovarian Cancer through Modulation of G 2M Phase Transition , 2006 .

[52]  Stephen L. Abrams,et al.  Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. , 2007, Biochimica et biophysica acta.

[53]  S. Cannistra,et al.  Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. , 2001, The American journal of pathology.