The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism

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• 作者：Olivier Calvayrac ; Julien Maziè ; res ; Sarah Figarol ; Claire Marty-Detraves ; Isabelle Raymond-Letron ; Emilie Bousquet ; Magali Farella ; Estelle Clermont-Taranchon ; Julie Milia ; Isabelle Rouquette ; Nicolas Guibert ; Amé ; lie Lusque ; Jacques Cadranel ; Nathalie Mathiot ; Ariel Savina ; Anne Pradines and Gilles Favre
• 刊名：EMBO Molecular Medicine
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：9
• 期：2
• 页码：238-250
• 全文大小：1862K
• ISSN：1757-4684

文摘

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 EGFR^L858R transgenic 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.