Abstract 4026: Mechanism of cisplatin resistance and enhanced cell migration in cervical cancer cells expressing PIK3CA-E545K mutation

Abstract

Abstract Platinum-based drugs, in particular cisplatin, are among the most widely used chemotherapeutic agents, used in the treatment of a wide array of solid malignancies. Despite initial therapeutic success, cisplatin treatment often results in the development of resistance, which can lead to therapeutic failure. Despite significant advances in understanding mechanisms of cisplatin resistance in other tumor sites, there are substantial gaps in our molecular knowledge of resistance in cervical cancer. Our group has examined the role of the PI3K/AKT/mTOR pathway in cervical cancer patients treated with cisplatin and radiation therapy. The PI3K/AKT/mTOR pathway is a promising therapeutic target because it is activated in several human cancers, which is frequently mediated by “hotspot” mutations including E542K, E545K and H1047R in the PIK3CA gene. Moreover, multiple PI3K/AKT/mTOR pathway inhibitors have been developed and are currently being evaluated in clinical trials. We previously reported that PIK3CA mutation in patients with early stage (IB/II) cervical cancer was associated with poor survival after treatment with radiation and cisplatin (McIntyre et al. Gynecol Oncol. 2013, PMID: 23266353), and that PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin or cisplatin plus radiation and results in a more migratory phenotype than cell lines with wild type-PIK3CA. Moreover, these phenotypes were reversed by the PI3K inhibitor GDC-0941 (Wani et al. Oncotarget. 2016, PMID: 27489350). The aim of the present study is to explore the mechanism of cisplatin resistance and enhanced migration in cervical cancer cells engineered to express PIK3CA-E545K mutation. Gene expression analysis identified 161 genes that were up regulated and 189 that were down regulated in cervical cancer cells stably expressing PIK3CA-E545K, some of which are involved in pathways relevant to cisplatin resistance. On further validation, we found that Fibronectin1 (FN1) was upregulated at both the mRNA and protein level in cervical cancer cells expressing PIK3CA-E545K. FN1 is a glycoprotein that is widely expressed in multiple cell types and is involved in cellular adhesion and migration. Recent studies have reported that FN1 might have a role in regulating chemoresistance in tumors. However, the effect of FN1 on cisplatin resistance in cervical cancer cells expressing E545K mutation has not been investigated. The present study aims to determine the effect of FN1 expression on cisplatin resistance in cervical cancer cells expressing the PIK3CA-E545K mutation and to explore potential mechanisms of cisplatin resistance and enhanced cell migration in cervical cancer cells. Citation Format: Arjumand Wani, Shiekh Tanveer Ahmad, Nicholas Jette, Siddhartha Goutam, Corinne M. Doll, Susan P. Miller. Mechanism of cisplatin resistance and enhanced cell migration in cervical cancer cells expressing PIK3CA-E545K mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4026.