Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells

Abstract

BackgroundOvarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance.MethodsHere we target EGFR, c-Src and Met individually or in combination with carboplatin, using Gefitinib, Dasatinib and Crizotinib respectively, in a panel of carboplatin-sensitive (OVCAR-3, IGROV-1 and A2780) and carboplatin-resistant cells (SKOV-3 and EFO-21). We studied the ability of the most potent combination to induce apoptosis, regulate migration, invasion and to modulate the activation of proliferation and survival proteins.ResultsCrizotinib, Dasatinib and Gefitinib, alone or in combination with carboplatin, showed a cell-specific cytotoxic synergy in ovarian cancer cells. The Dasatinib plus Gefitinib combination was synergistic in OVCAR-3, SKOV-3 and, in IGROV-1 cells (high concentrations). This combination was unable to induce apoptosis but suppressed cell migration, invasion and the activation of EGFR, Erk, c-Src and Akt compared to single treatments.ConclusionsCombining carboplatin with kinase inhibitors lead to synergistic interactions in a cell-specific manner. Unlike platinum-based combinations, mixing Dasatinib with Gefitinib led to cytotoxic activity, inhibition of cell migration and invasion. Thus, the Dasatinib + Gefitinib combination presents anti-tumour properties that are superior to those of platinum-based combinations, indicating that it may well represent a promising new treatment modality to be tested in the clinic.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-017-0319-2) contains supplementary material, which is available to authorized users.

Paclitaxel-Induced Src Activation Is Inhibited by Dasatinib Treatment, Independently of Cancer Stem Cell Properties, in a Mouse Model of Ovarian Cancer

“…In this study, we report significantly high expression of phosphorylated Src in high-stage ovarian tumours compared to normal/benign and low-stage ovarian tumours. Src overexpression has been reported in various cancers, including ovarian cancer, during the progressive stages and is known to promote cancer cell survival and growth leading to poor survival in patients [22,23]. We also demonstrate that ascites-derived tumour cells, isolated from chemotherapy-treated recurrent ovarian cancer patients, have significantly high expression of activated Src compared to ascites-derived tumour cells of chemonaïve patients.…”

“…This suggests that activated Src may have a potential role in facilitating chemoresistance which is associated with recurrence in ovarian cancer. Given that Src signalling has been previously implicated in promoting chemoresistance in ovarian cancer [13,23,24], in the present study we aimed to investigate the CSC-mediated anti-tumour activity of Dasatinib, alone and in combination with paclitaxel in vitro and in vivo.…”

Global view of a drug-sensitivity gene network

“…EPHA2 is also the target of Dasatinib. Interestingly, the combination of Dasatinib and Gefitinib (an EGFR inhibitor) presents anti-tumor properties that are superior to those of platinum-based combinations, indicating that this combination may be a promising new treatment modality to be tested in the clinic [ 33 ]. We extracted a subnetwork of epidermal growth factor receptor (EGFR) gene and its neighbor nodes from the HPRD network (Figure 5D ).…”

Tyrosine Kinase Inhibition in HPV-related Squamous Cell Carcinoma Reveals Beneficial Expression of cKIT and Src

“…However, it has been shown that Src family kinases are activated in cetuximab-resistant cells that could be resensitized to cetuximab by using dasatinib (55). Another option would therefore be a combination of Src inhibition and selective EGFR inhibition (56). Moreover, the activation of EGFR might be a regulator of dasatinib mediated effects.…”