Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein-protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein-protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.

https://www.zora.uzh.ch/id/eprint/165500/1/30476243.pdf

STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.

Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

https://science.sciencemag.org/content/sci/early/2004/04/29/science.1099314.full.pdf

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

Cell signaling by receptor-tyrosine kinases

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

The Rho small GTPases regulate a variety of cellular functions, including proliferation, differentiation, vesicle trafficking, gene expression, adhesion, and motility. Among their well established essential roles is that of organizing the actin cytoskeleton, and this aspect of Rho GTPase function has led to the identification of important roles for various Rho family GTPases in a variety of actin-dependent cellular processes, including cell shape change, adhesion, and migration. As critical regulators of these actin-mediated processes, the Rho GTPases also function as essential regulators of many developmental processes. The morphogenesis of tissues in all developing multi-cellular organisms requires precise changes in cell shape and cell movements that depend on the various Rho GTPases. This has been observed in studies using sevefigureral different developmental model systems, including flies, worms, frogs, and mice. Here, we review the literature reporting functions for Rho GTPases and their associated signaling components in the context of embryonic development, adult physiology, and pathogenesis. In particular, the focus of the studies described here is on the mouse system, where transgenic and “knockout” strategies have played an especially important role in elucidating the in vivo organization and function of the various Rho signaling pathways.

Genetic Analysis of Rho Protein Function in Mice

A method for determining the responsiveness of a tumor to treatments with the epidermal growth factor receptor as a target

Modulation of CREB activity by the Rho GTPase determines cell size during embryonic development

Cancer treatment with a combination of an Epidermal Growth Factor Receptor tyrosine kinase inhibitor and an Interleukin-6 inhibitor.

Methods of assessing therapeutic benefits of patients having cancers resistant to epidermal growth factor receptor kinase inhibitors

L'invention porte sur un procede permettant de determiner la reponse d'un cancer a un traitement par le recepteur du facteur de croissance epidermique (EGFR). Dans une execution preferee, la presence d'au moins une variance dans le domaine kinasique du gene erbB 1 confere une sensibilite a l'inhibiteur gefitinib de la tyrosine kinase. Ainsi, un essai diagnostique recherchant ces mutations permettra d'administrer le gefitinib, l'erlotinib et d'autres inhibiteurs de la tyrosine kinase tyrosine a ceux des patients les plus susceptibles de repondre au medicament.

Raffaella Sordella

Papers

Genetic Analysis of Rho Protein Function in Mice

A method for determining the responsiveness of a tumor to treatments with the epidermal growth factor receptor as a target

Modulation of CREB activity by the Rho GTPase determines cell size during embryonic development

Methods of assessing therapeutic benefits of patients having cancers resistant to epidermal growth factor receptor kinase inhibitors

Procede permettant de determiner la reponse d'un cancer a des traitements cibles par le recepteur du facteur de croissance epidermique