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

Abstract
SRC tyrosine kinase is often overexpressed and activated in advanced, poor-prognosis ovarian tumors. Preclinical studies have indicated that targeted SRC inhibitors may be beneficial for treating this disease. The SAPPROC trial explored the effects of adding the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for platinum-resistant ovarian cancer; however, this combination did not improve progression-free survival (PFS) for affected women. In our study, we aimed to uncover the mechanisms behind resistance to SRC inhibitors in ovarian cancer cells. Utilizing two complementary approaches—a targeted siRNA screen of tumor suppressor genes and a phospho-receptor tyrosine kinase array—we found that the activation of MAPK signaling, driven by decreased expression of NF1 (neurofibromin) or the overexpression of HER2 and the insulin receptor, contributes to resistance against AZD0530. Specifically, knocking down NF1 in two ovarian cancer cell lines led to resistance to AZD0530, which was associated with activated MEK and ERK signaling pathways. Moreover, silencing HER2 and the insulin receptor partially resensitized AZD0530-resistant cells, linked to reduced phosphorylation of MEK and ERK. Our findings also revealed a synergistic effect when combining SRC and MEK inhibitors in both AZD0530-sensitive and -resistant cells, with MEK inhibition being sufficient to fully resensitize the resistant cells. This research provides a preclinical rationale for combining SRC and MEK inhibitors in ovarian cancer treatment and emphasizes the importance of AZD0530 biomarker-driven patient selection for clinical trials.