title: Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection.
abstract: The phosphoinositide 3-kinase (PI3K) signaling pathway is significantly altered in a wide variety of human cancers, driving cancer cell growth and survival. Consequently, a large number of PI3K inhibitors are now in clinical development. To begin to improve the selection of patients for treatment with PI3K inhibitors and to identify de novo determinants of patient response, we sought to identify and characterize candidate genomic and phosphoproteomic biomarkers predictive of response to the selective PI3K inhibitor, GDC-0941, using the NCI-60 human tumor cell line collection. In this study, sixty diverse tumor cell lines were exposed to GDC-0941 and classified by GI(50) value as sensitive or resistant. The most sensitive and resistant cell lines were analyzed for their baseline levels of gene expression and phosphorylation of key signaling nodes. Phosphorylation or activation status of both the PI3K-Akt signaling axis and PARP were correlated with in vitro response to GDC-0941. A gene expression signature associated with in vitro sensitivity to GDC-0941 was also identified. Furthermore, in vitro siRNA-mediated silencing of two genes in this signature, OGT and DDN, validated their role in modulating sensitivity to GDC-0941 in numerous cell lines and begins to provide biological insights into their role as chemosensitizers. These candidate biomarkers will offer useful tools to begin a more thorough understanding of determinants of patient response to PI3K inhibitors and merit exploration in human cancer patients treated with PI3K inhibitors.
authors.affiliation: Genomic Health, Inc, Redwood City, California, United States of America.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kwei
authors.forename: Joffre B
authors.initials: JB
authors.lastname: Baker
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pelham
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D064447:Checkpoint Kinase 2; D020893:Receptor, ErbB-3; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000117:Acetylglucosamine