Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src frequently occurs in human tumorsand is linked to enhanced tumor growth. In experimental systems this synergistic growth requires EGF-dependent association of c-Src with the EGFR and phosphorylation of Tyr-845 of the receptor by c-Src. A search for signaling mediators of Tyr(P)-845 revealed that mitochondrial cytochrome c oxidase subunit II (CoxII) binds EGFR in a Tyr(P)-845-and EGF-dependent manner. In cells this association involves translocation of EGFR to the mitochondria, but regulation of this process is ill-defined. The current study demonstrates that c-Src translocates to the mitochondria with similar kinetics as EGFR and that the catalytic activity of EGFR and c-Src as well as endocytosis and a mitochondrial localization signal are required for these events. CoxII can be phosphorylated by EGFR and c-Src, and EGF stimulation reduces Cox activity and cellular ATP, an event that is dependent in large part on EGFR localized to the mitochondria. These findings suggest EGFR plays a novel role in modulating mitochondrial function via its association with, and modification of CoxII. The epidermal growth factor receptor (EGFR)2 is overexpressed in many cancers including breast cancers, where its overexpression is associated with a poor prognosis (1, 2), yet EGFR alone when overexpressed in fibroblasts is a weak oncogene (3). The non-receptor-tyrosine kinase, c-Src, is also overexpressed in ϳ70% of breast cancers (4), suggesting that EGFR and c-Src may function cooperatively in cancers that co-overexpress both kinases (1). Investigations in murine fibroblasts and in human breast cancer cells have revealed synergistic increases in DNA synthesis, soft agar colony growth, and tumor formation in nude mice when EGFR and c-Src are co-overexpressed as compared with cells overexpressing EGFR or c-Src alone (5, 6). These synergistic increases are dependent upon EGF stimulation, the kinase activity of c-Src, and c-Src phosphorylation of tyrosine 845 (Tyr-845) (7), a highly conserved residue in the activation loop of the catalytic domain of the EGFR. Substitution of a phenylalanine for a tyrosine at position 845 (Y845F) ablates EGF-induced DNA synthesis (even in the presence of overexpressed c-Src) without affecting the intrinsic kinase activity of the EGFR or its ability to phosphorylate canonical downstream substrates (13). Combined, these results suggest that phosphorylated Tyr-845 (Tyr(P)-845) elicits a critical mitogenic signal when EGFR and c-Src are co-overexpressed that is mediated through unconventional substrates.Subsequent efforts to identify mediators of the Tyr(P)-845 EGFR mitogenic signal revealed that phosphorylation and transcriptional activation of Stat5b are dependent on Tyr(P)-845 and that Stat5b is required for EGF-induced DNA synthesis (8). Phage display screening of a human breast cancer tissue library also identified cytochrome c oxidase subunit II (CoxII) as a protein that binds the EGFR in a Tyr(P)-845-and EGF-dependent...

Although scarring was different across some regions, only scarring in Asian studies comparing patients displayed a statistically significant difference. A regional effect explained the heterogeneity observed in the overall estimate for patients and partly for renal units. The greatest risk of renal scarring may be imparted by the presence of vesicoureteral reflux.

Recent studies have challenged the traditional paradigm of aggressive vesicoureteral reflux management with surgery or antibiotic prophylaxis. In light of these findings, pediatric urologists will need to reexamine treatment modalities for vesicoureteral reflux.

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Objective: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients. Methods: Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 hours preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 hours following the second dose. Results: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥60%. Conclusions: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.