RESUMEN
In subtypes and late stages of leukemias driven by the tyrosine kinase fusion protein Bcr-Abl, signaling by the Src family kinases (SFKs) critically contributes to the leukemic phenotype. We performed global tyrosine phosphoprofiling by quantitative mass spectrometry of Bcr-Abl-transformed cells in which the activities of the SFKs were perturbed to build a detailed context-dependent network of cancer signaling. Perturbation of the SFKs Lyn and Hck with genetics or inhibitors revealed Bcr-Abl downstream phosphorylation events either mediated by or independent of SFKs. We identified multiple negative feedback mechanisms within the network of signaling events affected by Bcr-Abl and SFKs and found that Bcr-Abl attenuated these inhibitory mechanisms. The C-terminal Src kinase (Csk)-binding protein Pag1 (also known as Cbp) and the tyrosine phosphatase Ptpn18 both mediated negative feedback to SFKs. We observed Bcr-Abl-mediated phosphorylation of the phosphatase Shp2 (Ptpn11), and this may contribute to the suppression of these negative feedback mechanisms to promote Bcr-Abl-activated SFK signaling. Csk and a kinase-deficient Csk mutant both produced similar globally repressive signaling consequences, suggesting a critical role for the adaptor protein function of Csk in its inhibition of Bcr-Abl and SFK signaling. The identified Bcr-Abl-activated SFK regulatory mechanisms are candidates for dysregulation during leukemia progression and acquisition of SFK-mediated drug resistance.
Asunto(s)
Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/metabolismo , Leucemia/enzimología , Proteínas Tirosina Quinasas/metabolismo , Proteómica , Transducción de Señal , Familia-src Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Tirosina Quinasa CSK , Línea Celular Transformada , Línea Celular Tumoral , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia/tratamiento farmacológico , Leucemia/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fosforilación , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/genéticaRESUMEN
BACKGROUND: Pancreatic cancers of the body and tail (BT) appear to have poorer survival compared with head (HD) lesions. We hypothesized that potential disparities in outcome may be related to tumor location. Our objective was to examine the relationship between tumor location and survival. METHODS: The Surveillance, Epidemiology, and End Results registry identified 33,752 patients with pancreatic adenocarcinoma and 6443 patients who underwent cancer-directed surgery between 1988 and 2004. Differences in survival and relationships between tumor location and clinical factors were assessed. Multivariate analysis was performed to determine the prognostic significance of tumor location. RESULTS: Median survival for the entire cohort was five months and was significantly lower for BT compared to HD lesions (four vs. six months, p<0.001). Distant metastases (67% vs. 36%, p<0.001) were greater and cancer-directed surgery (16% vs. 30%, p<0.001) was lower for BT tumors. Of 6443 resected patients, HD patients (n=5118) were younger, had a greater number of harvested lymph nodes, were more likely to be lymph node-positive, and had a higher proportion of T3/T4 lesions. Significant univariate predictors of survival included age, T-stage, number of positive and harvested lymph nodes. On multivariate analysis, BT location was a significant prognostic factor for decreased survival (OR 1.11, 95% CI 1.00-1.23, p=0.05). DISCUSSION: Pancreatic BT cancers have a lower rate of resectability and poorer overall survival compared to HD lesions. Prospective large-cohort studies may definitively prove that tumor location is a prognostic factor for survival in patients with pancreatic cancer.