The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells

Abstract

BackgroundMalignant pleural mesothelioma is an aggressive cancer, characterized by rapid progression and high mortality. Persistence of tumor-initiating cells (TICs, or cancer stem cells) after cytotoxic drug treatment is responsible for tumor relapse, and represents one of the main reasons for the poor prognosis of mesothelioma. In fact, identification of the molecules affecting TIC viability is still a significant challenge.MethodsTIC-enriched cultures were obtained from 10 human malignant pleural mesotheliomas and cultured in vitro. Three fully characterized tumorigenic cultures, named MM1, MM3, and MM4, were selected and used to assess antiproliferative effects of the multi-kinase inhibitor sorafenib. Cell viability was investigated by MTT assay, and cell cycle analysis as well as induction of apoptosis were determined by flow cytometry. Western blotting was performed to reveal the modulation of protein expression and the phosphorylation status of pathways associated with sorafenib treatment.ResultsWe analyzed the molecular mechanisms of the antiproliferative effects of sorafenib in mesothelioma TIC cultures. Sorafenib inhibited cell cycle progression in all cultures, but only in MM3 and MM4 cells was this effect associated with Mcl-1-dependent apoptosis. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF) causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt, and STAT3 phosphorylation. These effects were abolished by sorafenib only in bFGF-treated cells, while a modest inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGF receptor (FGFR) inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib.Moreover, in MM1 cells, which release high levels of bFGF and showed autocrine activation of FGFR1 and constitutive phosphorylation/activation of MEK-ERK1/2, sorafenib induced a more effective antiproliferative response, confirming that the main target of the drug is the inhibition of FGFR1 activity.ConclusionsThese results suggest that, in malignant pleural mesothelioma TICs, bFGF signaling is the main target of the antiproliferative response of sorafenib, acting directly on the FGFR1 activation. Patients with constitutive FGFR1 activation via an autocrine loop may be more sensitive to sorafenib treatment and the analysis of this possibility warrants further clinical investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0573-7) contains supplementary material, which is available to authorized users.

A novel 2‐aminobenzimidazole‐based compound Jzu 17 exhibits anti‐angiogenesis effects by targeting VEGFR‐2 signalling

“…We thus used an in vitro kinase assay to examine the effects of Jzu 17, sunitinib, and sorafenib on the intrinsic TK activity of VEGFR‐2. Sunitinib (Latham et al, ) and sorafenib (Pattarozzi et al, ) are inhibitors of many RTKs, which also suppress the kinase activity of bFGFR. The effects of these compounds on bFGFR1 kinase activity were also determined.…”

A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma

“…Multiple members of the miR-15/16 family may be targeted with microRNA mimics, whereas FGFRs and Bcl-2 have the advantage of being druggable. FGFR inhibition has shown promising effects in various preclinical studies (Dey et al, 2010;Maruyama-Takahashi et al, 2008;Metzner et al, 2011;Pattarozzi et al, 2017;Qing et al, 2009;Schelch et al, 2014) and is currently being tested in patients with solid tumors, especially in those with known FGFR overexpression or genomic alterations ( Katoh and Nakagama, 2014). In mesothelioma, a phase lll study using the multi-RTK inhibitor nintedanib (NCT01907100) and a phase lb trial using the FGFR ligand trap GSK3052230 in combination with first-line chemotherapy (NCT01868022) are ongoing.…”

Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

“…For example, studies on CSC from glioblastoma, breast cancer or osteosarcoma (119,(121)(122)(123), demonstrated a higher sensitivity of this subpopulation to metformin, as compared to "differentiated" tumor cells, determining the development of a drug repositioning approach (124,125). In particular, while it is well-accepted that stem-like cells are particularly resistant to classical cytotoxic drugs due to the overexpression of drug-extruding pumps and DNA-repairing enzymes (110), in CSC cultures from different tumors the sensitivity to molecular-targeted drugs, in particular to tyrosine kinase inhibitors, is retained (114,126).…”