PD28-09 ABNORMAL HER2 AND HER3 SIGNALLING IN PROSTATE CANCER: POTENTIALS FOR CLINICAL APPLICATION.

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I1 Apr 2016PD28-09 ABNORMAL HER2 AND HER3 SIGNALLING IN PROSTATE CANCER: POTENTIALS FOR CLINICAL APPLICATION. Kasturi Rao, Massar Alsamraae, Luke Gaughan, Craig Robson, and Stuart McCracken Kasturi RaoKasturi Rao More articles by this author , Massar AlsamraaeMassar Alsamraae More articles by this author , Luke GaughanLuke Gaughan More articles by this author , Craig RobsonCraig Robson More articles by this author , and Stuart McCrackenStuart McCracken More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.396AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES HER family members (EGFR, HER2, HER3 and HER4) have been associated with the development of castrate-resistant prostate cancer. Previous research has focussed on targeting EGFR and HER2 receptors, however the role of HER3 in driving PI3K/Akt signalling and mediating drug resistance has shifted the attention towards this signalling partner. The use of pan-inhibitors targeting multiple members of the HER receptor family represents an attractive therapeutic approach in prostate cancer. METHODS We performed immunohistochemistry on human prostate samples, plus immunoblotting with nuclear-cytoplasmic extractions, luciferase reporter assays and proliferation/migration/invasion assays on prostate cancer cell lines. Utilized prostate cell line models included: androgen sensitive disease (LNCaP); an androgen independent derived line (LNCaP-AI); and cell line models of acquired resistance to Lapatinib (LNCaP-LapR) and Enzalutamide (LNCaP-EnzR). We have also developed HER2 and HER3 overexpressing stable cell lines using lentiviral technology. RESULTS We analysed the expression of HER2 and HER3 receptors and their downstream targets using tissue microarrays. We have shown strong correlations between HER2 and HER3 cytoplasmic and nuclear expression with poor prognostic disease. Part of the analysis consists of matched paired patient tissue samples (before and after relapse on conventional anti-androgen treatment). We have also shown in our cell line models that HER2/HER3 signalling: increases androgen receptor activity; increases downstream MAP Kinase and PI3 Kinase signalling activity; and increases cell proliferation, migration and invasion. The addition of a pan-HER family inhibitor inhibited all of these activities and also reduced nuclear translocation of HER2 and HER3, with prevention of chromatin binding. Finally, both Lapatinib and Enzalutamide resistant cell lines demonstrated increased HER2 and HER3 activity, subsequently shown to be sensitive to pan-HER inhibition. CONCLUSIONS HER2 and HER3 play a prominent role in advanced prostate cancer. We have also demonstrated the reduced activity of androgen receptor, plus PI3K and MAPK pathways downstream of the HER2/3 signalling pathways by the use of a novel pan-HER inhibitor. This pan-HER inhibitor has also reduced cellular activities important for cancer progression. The increased expression of HER2 and HER3 in both the Lapatinib and Enzalutamide resistant lines suggests that combination therapy of novel anti-androgens with pan-HER inhibitiors may delay cancer progression in prostate cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e657 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kasturi Rao More articles by this author Massar Alsamraae More articles by this author Luke Gaughan More articles by this author Craig Robson More articles by this author Stuart McCracken More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...