Ance. On the other hand, in spite of this high response price, all sufferers usually relapse using a median delay of 12 months. Amongst the handful of identified mechanisms of main resistance, low expression levels with the proapoptotic protein BIM happen to be revealed as a great predictor of nonresponsiveness to targeted therapy in EGFRmutated cells and sufferers (Faber et al, 2011), and equivalent observations have been reported for the RAS GTPaseactivating protein NF1 (de Bruin et al, 2014). Lots of mechanisms of acquired resistance have already been 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 to the improvement of newgeneration drugs (Cross et al, 2014) that happen to be offered sequentially soon after EGFRTKI failure. Resistance mechanisms to EGFRTKI could be mediated by a bypass reactivation of 1 or many key proliferation and survival signaling pathways downstream from EGFR, primarily PI3K (phosphatidylinositol 3kinase)AKT (Engelman et al, 2007), MEK1 2 three four 5 six 7 8Inserm, CD161 Autophagy 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; E mail: [email protected] Corresponding author. Tel: 33 5 31 15 52 01; Email: [email protected] These Talniflumate Inhibitor Authors contributed equally to this workEMBO Molecular Medicine Vol 9 No 2 2016 The Authors. Published under the terms in 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 is absolutely no authorized predictive biomarker in a position to predict tumor sensitivity to EGFRTKI given that the majority of the resistance mechanisms are acquired during tumor remedy. RHOB is really a RASrelated monomeric GTPase that displays tumor suppressor activity in NSCLC. RHOB expression is downregulated in aggressive tumors, and we’ve shown that the loss of RHOB is associated with decreased overall survival in two independent series of sufferers (Calvayrac et al, 2014). Extra lately, we showed that RHOB levels aren’t only a strong prognostic factor for NSCLC but that its downregulation is also 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; having said that, we’ve got shown that RHOB controls cell survival and invasion by way of PP2Amediated AKT dephosphorylation (Bousquet et al, 2009). RHOB is definitely an early response gene.