Ance. However, regardless of this high response price, all patients commonly relapse using a median delay of 12 months. Among the couple of identified mechanisms of primary resistance, low expression levels with the proapoptotic protein BIM have already been revealed as a fantastic predictor of nonresponsiveness to targeted therapy in EGFRmutated cells and individuals (Faber et al, 2011), and related observations happen to be reported for the RAS GTPaseactivating protein NF1 (de Bruin et al, 2014). Numerous mechanisms of acquired resistance happen to be elucidated so far, such as the T790M gatekeeper mutation (Nguyen et al, 2009), amplification of either the MET oncogene ( Engelman et al, 2007) or HER2 (Takezawa et al, 2012), or epithelialtomesenchymal transition (EMT) (Thomson et al, 2005). These have led towards the development of newgeneration drugs (Cross et al, 2014) which can be provided sequentially immediately after EGFRTKI failure. Resistance mechanisms to EGFRTKI could possibly be mediated by a bypass reactivation of one or many key proliferation and survival signaling pathways downstream from EGFR, mostly PI3K (phosphatidylinositol 3kinase)AKT (Engelman et al, 2007), MEK1 two three four five six 7 8Inserm, Centre de Recherche en Canc ologie de Toulouse, CRCT UMR1037, Toulouse, France UniversitPaul Sabatier, Toulouse, France CHU Toulouse, IUCTRangueilLarrey, Service de Pneumologie, Toulouse, France Laboratoire d’Histopathologie, UPSINPENVT, UMS006, Universitde Toulouse, Toulouse, France Laboratoire de Biologie M icale Oncologique, Institut Claudius Regaud, IUCTOncopole, Toulouse, France Departement d’AnatomoCytopathologie, CHU de Toulouse, IUCTOncopole, Toulouse, France Institut Claudius Regaud, IUCTOncopole, Bureau des Essais Cliniques, Cellule Biostatistiques, Toulouse, France Sorbonne Universit , UPMC Univ. Paris 06, GRC n4, Theranoscan, Paris, APHP, H ital Tenon, Service de Pneumologie, Paris, France Institut Roche, Roche SAS, BoulogneBillancourt, France Corresponding author. Tel: 33 five 67 77 18 37; Email: [email protected] Corresponding author. Tel: 33 five 31 15 52 01; E mail: [email protected] These authors contributed equally to this workEMBO Molecular Medicine Vol 9 No 2 2016 The Authors. Published under the terms with the CC BY 4.0 licenseOlivier Calvayrac et alRHOB confers resistance to EGFRTKIEMBO Molecular Medicine(mitogenactivated protein kinase kinase)ERK (extracellular signalregulated kinase) (Ercan et al, 2012), or STAT (signal transducer and activator of transcription) pathways (Lee et al, 2014), among other individuals. To date, there isn’t any authorized predictive biomarker in a position to predict tumor sensitivity to EGFRTKI given that the majority of the resistance mechanisms are acquired for the duration of tumor remedy. RHOB can be a RASrelated monomeric GTPase that displays tumor suppressor activity in NSCLC. RHOB expression is downregulated in aggressive tumors, and we’ve got shown that the loss of RHOB is linked with decreased overall survival in two independent series of sufferers (Calvayrac et al, 2014). Much more recently, we showed that RHOB levels Ned 19 site aren’t only a powerful prognostic element for NSCLC but that its downregulation can also be crucial for the acquisition of an aggressive phenotype of adenocarcinoma in an EGFRL858Rinduced tumor model in mice (Calvayrac et al, 2014). The underlying mechanism of RHOBmediated tumor suppression is only partially understood; nevertheless, we’ve shown that RHOB controls cell survival and invasion by means of PP2Amediated AKT dephosphorylation (Bousquet et al, 2009). RHOB is definitely an early response gene.