Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells
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Wani Arjumand1,2,4, Cole D. Merry1,2, Chen Wang1,2, Elias Saba1,2, John B. McIntyre3, Shujuan Fang1,2, Elizabeth Kornaga3, Prafull Ghatage4, Corinne M. Doll2,4, Susan P. Lees-Miller1,2,4
1Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
2Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
3Translational Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
4Department of Oncology, University of Calgary, Calgary, Alberta, Canada
Susan P. Lees-Miller, email: email@example.com
Corinne Doll, email: Corinne.Doll@albertahealthservices.ca
Keywords: PI3K pathway, PIK3CA-E545K, Akt, GDC-0941, cisplatin
Received: February 11, 2016 Accepted: July 18, 2016 Published: July 30, 2016
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.
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