The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors.

In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models.

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations.

S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo.

Only a subset of Met-activated pathways are required to sustain oncogene addiction.

Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer.

Only a subset of Met-activated pathways are required to sustain oncogene addiction.

Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer.

Three-dimensional in vitro anglogenesis in the rat aortic ring model.

Angiogenesis is a complex sequential process involving endothelial activation, basement membrane degradation, endothelial sprouting from the parent vessel, invasion of the extracellular matrix, endothelial proliferation, vessel elongation, branching, anastomosis, increases in vessel diameter, basement membrane formation, pericyte acquisition, and remodelling. Most in vitro angiogenesis assays are two-dimensional and measure only one facet of this process, generally endothelial proliferation, migration, or tube formation. The two-dimensional nature of the assays also ignores the differences in endothelial phenotype seen in three-dimensional models and in vivo.

Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist.

The role of adhesion molecules, such as alphav integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule alphav integrin antagonist, to investigate the role of integrin-signaling in the survival of populations of quiescent human HT-29 and HCT 116 colon carcinoma cells. S 34961 at 1 microM induced detachment, but cells retained viability, existing as clusters.