Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

Therapeutic Vulnerability to ATR Inhibition in Concurrent <i>NF1</i> and <i>ATRX</i>-Deficient/ALT-Positive High-Grade Solid Tumors

Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and the presence of alternative lengthening of telomeres (ALT). We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. Cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), an NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), an NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors, with or without a MEK inhibitor or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line demonstrated sensitivity to ATR inhibition, but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors

Outcome of medical and surgical therapy of GERD: predictive role of quality of life scores and instrumental evaluation

ABSTRACT Introduction Aim of this study is to determine whether quality of life (QoL) assessment in association with instrumental evaluation can help to identify factors predictive of outcome both in surgically and medically treated GERD patients. Methods Between January 2005 and June 2010, 301 patients affected with GERD were included in the study. QoL was evaluated by means of GERD-HRQL and SF-36 questionnaires administered before treatment, at 6 months, at 1 year follow-up and at the end of the study. The multivariate analysis was used to detect if variables such as sex, age, heartburn, acid regurgitation, dysphagia, presence of esophagitis, percentage of total time at pH < 4, symptom index score (SI), the SF-36 and HRQL scores before treatment, at 6 months and 1 year could affect the QoL questionnaires scores at the end of the study. Results One hundred forty-seven patients were included in the surgical group and 154 in the medical group. No differences with regard to gender, age, mean SF-36 and HRQL scores before treatment were documented. At the end of the study, quality of life was significantly improved for SF-36 and HRQL scores, either for surgical or medical group. The multivariate analysis showed no factors individually affected the SF-36 and the HRQL scores, but symptom index score (SI) and QoL questionnaires scores at 6 months and 1 year follow-up. Conclusions The combined use of pHmetry with evaluation of SI and QoL questionnaires can predict the outcome of GERD patients managed either by medical or surgical therapy