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

Abstract

Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer.

Mechanisms of Taxane Resistance

“…Evidence of c-Src playing a role in cell proliferation, cell adhesion, metastasis, and angiogenesis characterizes it as a proto-oncogene and suggests a therapeutic target for reducing tumor growth and combating taxane resistance [ 257 ]. In addition, Src protein levels and activation were increased after PTX treatment in OC cell lines and ascites of HGSOC patients [ 259 ]. Inhibition of SFKs with dasatinib reduces proliferation, induces autophagy and apoptosis in ovarian cancer cells, and reduces tumor growth in mouse models [ 260 , 261 , 262 ].…”

Polarity switching of ovarian cancer cell clusters via SRC family kinase is involved in the peritoneal dissemination

“…In vitro and in vivo studies using OC cell lines showed that dasatinib combined with gefitinib suppressed growth and invasion of OC cells, 27 a specific SFK inhibitor PP2 suppressed anchorage‐dependent and ‐independent growth of phospho‐SFK–positive OC cells, 28 and dasatinib suppressed SFK activation induced by paclitaxel with a reduced tendency of invasion. 29 Conversely, clinical trials showed that dasatinib single‐agent treatment did not have clinical efficacy, 30 and saracatinib, an SFK inhibitor, did not improve the effect of weekly paclitaxel in platinum‐resistant OC. 31 Using OC organoid, it was shown that dasatinib inhibited organoids' adhesion to ECM and suppressed the establishment of peritoneal metastasis, possibly through polarity‐switching inhibition, while the tumor volume was not reduced once colonized and tumor formed, being consistent with the clinical trial.…”

Clinical Efficacy of Fuzheng Guben Anticancer Decoction Combined with Taxol in Treating Ovarian Carcinoma and Its Effect on Complication Incidence

“…e clinical treatment effect of patients in both groups was evaluated referring to the Response Evaluation Criteria in Solid Tumors (RECICT) [14] as follows. It was considered as complete response (CR) if the patients' lesion disappeared completely or for 4 weeks; partial response (PR) if the lesion was shrunk to over 30% for over 4 weeks; stable disease (SD) if the lesion was shrunk to less than 30% or increased by less than 20%; and progressive disease (PD) if the lesion was increased by more than 20% or there were new lesions.…”