Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

McGivern, N., El-Helali, A., Mullan, P., Mcneish, I. A. , Paul Harkin, D., Kennedy, R. D. and McCabe, N. (2018) Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer. Oncotarget, 9(4), pp. 4722-4736. (doi: 10.18632/oncotarget.23524) (PMID:29435137) (PMCID:PMC5797008)

Abstract

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.

• Item Type: Articles
• Additional Information: This work was funded by Department for the Economy Northern Ireland and the European Sustainable Competitiveness Programme 2007–2013, European Regional Development Fund (ERDF) through Invest Northern Ireland.
• Keywords: MAPK, SRC, drug combination, ovarian cancer, resistance
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mcneish, Professor Iain
• Authors: McGivern, N., El-Helali, A., Mullan, P., Mcneish, I. A., Paul Harkin, D., Kennedy, R. D., and McCabe, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Published Online: 20 December 2017
• Copyright Holders: Copyright © 2017 McGivern at al.
• First Published: First published in Oncotarget 9(4):4722-4736
• Publisher Policy: Reproduced under a Creative Commons License