No abstract

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of alterations. Patients ( = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. BJG398 is active in patients with alterations in , resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status..

We have previously shown that CD82, a transmembrane protein of the tetraspanin superfamily is associated with EGFR and has a negative effect on EGF-induced signalling (Odintsova, E., Sugiura, T. and Berditchevski, F. (2000) Curr. Biol. 10, 1009-1012). Here we demonstrate that CD82 specifically attenuates ligand-induced dimerization of EGFR. The recombinant soluble large extracellular loop of CD82 has no effect on the dimerization thereby suggesting that other parts of the protein are required. Although CD82 is also associated with ErbB2 and ErbB3, ligand-induced assembly of the ErbB2-ErbB3 complexes is not affected in CD82-expressing cells. Furthermore, in contrast to the CD82-EGFR association, CD82-ErbB2 and CD82-ErbB3 complexes are stable in the presence of ErbB3 ligand. The effect of CD82 on the formation of EGFR dimers correlates with changes in compartmentalisation of the ErbB receptors on the plasma membrane. Expression of CD82 causes a significant increase in the amount of EGFR and ErbB2 in the light fractions of the sucrose gradient. This correlates with the increased surface expression of gangliosides GD1a and GM1 and redistribution of GD1a and EGFR on the plasma membrane. Furthermore, in CD82-expressing cells GD1a is co-localised with EGFR and the tetraspanin. Taken together our results offer a molecular mechanism of the attenuating activity of CD82 towards EGFR, whereby GD1a functions as a mediator of CD82-dependent compartmentalisation of the receptor.

Activation of the tumor necrosis factor -related apoptosisinducing ligand (TRAIL) receptor pathway is a promising therapeutic strategy to selectively eradicate cancer cells, including non -small cell lung cancer (NSCLC) cells. Recombinant human (rh) TRAIL/Apo-2L, a TRAIL-encoding adenovirus, and monoclonal antibodies directed against TRAIL receptors R1 and R2 were used to study cytotoxicity of TRAIL therapy in NSCLC cells. NSCLC cells showed differential sensitivity to TRAIL therapy, regard-