Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression–based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMS) with distinguishing features: CMS1 (MSI Immune, 14%), hypermutated, microsatellite unstable, strong immune activation; CMS2 (Canonical, 37%), epithelial, chromosomally unstable, marked WNT and MYC signaling activation; CMS3 (Metabolic, 13%), epithelial, evident metabolic dysregulation; and CMS4 (Mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion, and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intra-tumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC – with clear biological interpretability – and the basis for future clinical stratification and subtype–based targeted interventions.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

This is an author version of the article published on:Questa è la versione dell'autore dell'articolo: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. Nature. 2012 Jan 26;483(7387):100-3. doi: 10.1038/nature10868. The final version is available at: La versione definitiva è disponibile alla URL:http://www.nature.com/nature/journal/v483/n7387/full/nature10868.html . We therefore set out to screen a short hairpin RNA (shRNA) library representing the full complement of 518 human kinases 12 (the "kinome") and 17 additional kinase-related genes (Table S1) for genes whose inhibition confers sensitivity to PLX4032 in BRAF V600E mutant CRC. WiDr cells were infected with the lentiviral kinome shRNA collection and cultured in the absence or presence of PLX4032 for 10 and 18 days, respectively. After this, the relative abundance of shRNA vectors was determined by next generation sequencing of the bar code identifiers present in each shRNA vector (Fig. 1C, see methods). We arbitrarily considered only shRNA vectors that had been sequenced at least 300 times and which were depleted at least five-fold by the drug treatment. Fig. 1D shows that only very few of the 3388 shRNA vectors in the library met this stringent selection criterion, among which were three independent shRNA vectors targeting the Epidermal Growth FactorReceptor (EGFR, see Table S2 for all selected shRNAs). This suggested that suppression of EGFR synergizes with BRAF inhibition in these CRC cells. To validate this finding, we infected WiDr cells with each of these three EGFR shRNA vectors (all of which reduced EGFR levels (Fig. 1F)) and cultured these cells with or without PLX4032 for two weeks. . We therefore began by investigating a potential role of CDC25C in the activation of EGFR. We suppressed CDC25C in WiDr cells by shRNA and monitored levels of p-EGFR.We found that two independent shCDC25C vectors caused an increase in p-EGFR (Fig. 2E).Moreover, treatment of WiDr cells with PLX4032 inhibited phosphorylation of CDC25C at Thr48 (Fig. 2F), which has been shown to be required for its phosphatase activity 15 .Together, these data are consistent with a model in which BRAF inhibition leads to inhibition of MEK and ERK kinases, which in turn leads to a reduced activation of CDC25C. Inhibition of CDC25C in turn causes an increase in p-EGFR due to decreased dephosphorylation (Fig. 2E). Our data do not exclude that the related CDC25A and B or other phosphatases are also involved in this feedback regulation of EGFR.The EGFR is expressed primarily in epithelial cancers 17. Since melanomas are derived from the neural crest, we reasoned that the favourable response of melanomas to vemurafenib might result from the paucity of EGF receptors on these tumours and hence the 6 absence of the feedback activation of EGFR by BRAF inhibition. We compared EGFR expression in a panel of BRAF V600E mutant melanoma, colo...