title: The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism.
abstract: Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15.3 versus 5.6 months of progression-free survival). Moreover, a better response to EGFR-TKI was associated with low RHOB levels in a panel of lung tumor cell lines and in a lung-specific tetracycline-inducible EGFRL858Rtransgenic mouse model. High RHOB expression was also found to prevent erlotinib-induced AKT inhibition in vitro and in vivo Furthermore, a combination of the new-generation AKT inhibitor G594 with erlotinib induced tumor cell death in vitro and tumor regression in vivo in RHOB-positive cells. Our results support a role for RHOB/AKT signaling in the resistance to EGFR-TKI and propose RHOB as a potential predictor of patient response to EGFR-TKI treatment.
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Calvayrac
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France mazieres.j@chu-toulouse.fr favre.gilles@iuct-oncopole.fr.|Université Paul Sabatier, Toulouse, France.|CHU Toulouse, IUCT-Rangueil-Larrey, Service de Pneumologie, Toulouse, France.
authors.forename: Julien
authors.identifier: 0000-0002-5921-7613
authors.initials: J
authors.lastname: Mazières
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Figarol
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Marty-Detraves
authors.affiliation: Laboratoire d'Histopathologie, UPS-INP-ENVT, UMS006, Université de Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.affiliation: CHU Toulouse, IUCT-Rangueil-Larrey, Service de Pneumologie, Toulouse, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bousquet
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.|Laboratoire de Biologie Médicale Oncologique, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Farella
authors.affiliation: Departement d'Anatomo-Cytopathologie, CHU de Toulouse, IUCT-Oncopole, Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Clermont-Taranchon
authors.affiliation: Université Paul Sabatier, Toulouse, France.|CHU Toulouse, IUCT-Rangueil-Larrey, Service de Pneumologie, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Milia
authors.affiliation: Departement d'Anatomo-Cytopathologie, CHU de Toulouse, IUCT-Oncopole, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouquette
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.|CHU Toulouse, IUCT-Rangueil-Larrey, Service de Pneumologie, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guibert
authors.affiliation: Institut Claudius Regaud, IUCT-Oncopole, Bureau des Essais Cliniques, Cellule Biostatistiques, Toulouse, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Lusque
authors.affiliation: Sorbonne Universités UPMC Univ. Paris 06 GRC n°04 Theranoscan, Paris AP-HP, Hôpital Tenon, Service de Pneumologie, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Sorbonne Universités UPMC Univ. Paris 06 GRC n°04 Theranoscan, Paris AP-HP, Hôpital Tenon, Service de Pneumologie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mathiot
authors.affiliation: Institut Roche, Roche SAS, Boulogne-Billancourt, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.|Laboratoire de Biologie Médicale Oncologique, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pradines
authors.affiliation: Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France mazieres.j@chu-toulouse.fr favre.gilles@iuct-oncopole.fr.|Université Paul Sabatier, Toulouse, France.|Laboratoire de Biologie Médicale Oncologique, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Gilles
authors.identifier: 0000-0002-2344-1883
authors.initials: G
authors.lastname: Favre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000503:physiopathology*; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020743:rhoB GTP-Binding Protein
keywords: AKT; EGFR; RhoB; TKI; resistance