title: Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells.
abstract: The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA. The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA-E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Wani
authors.initials: W
authors.lastname: Arjumand
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Cole D
authors.initials: CD
authors.lastname: Merry
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Elias
authors.initials: E
authors.lastname: Saba
authors.affiliation: Translational Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: John B
authors.initials: JB
authors.lastname: McIntyre
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Fang
authors.affiliation: Translational Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kornaga
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Prafull
authors.initials: P
authors.lastname: Ghatage
authors.affiliation: Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Doll
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.|Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Lees-Miller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: Akt; GDC-0941; PI3K pathway; PIK3CA-E545K; cisplatin