Calvayrac Olivier, Mazières Julien, Figarol Sarah, Marty-Detraves Claire, Raymond-Letron Isabelle, Bousquet Emilie, Farella Magali, Clermont-Taranchon Estelle, Milia Julie, Rouquette Isabelle, Guibert Nicolas, Lusque Amélie, Cadranel Jacques, Mathiot Nathalie, Savina Ariel, Pradines Anne, Favre Gilles
Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France.
Université Paul Sabatier, Toulouse, France.
EMBO Mol Med. 2017 Feb;9(2):238-250. doi: 10.15252/emmm.201606646.
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 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.
尽管携带表皮生长因子受体（EGFR）突变的肺癌患者可从EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗中获益，但他们中的大多数人会很快复发。RHOB GTP酶在肺癌发生和EGFR信号通路中均起着关键作用；因此，我们推测它可能在对EGFR-TKI的反应中发挥作用。在一系列来自EGFR突变患者的样本中，我们发现RHOB低表达与对EGFR-TKI治疗的良好反应相关，而反应不佳则与RHOB高表达相关（无进展生存期分别为15.3个月和5.6个月）。此外，在一组肺癌细胞系和肺特异性四环素诱导型EGFR转基因小鼠模型中，对EGFR-TKI的更好反应与低RHOB水平相关。还发现高RHOB表达可在体外和体内阻止厄洛替尼诱导的AKT抑制。此外，新一代AKT抑制剂G594与厄洛替尼联合使用可在体外诱导肿瘤细胞死亡，并在体内使RHOB阳性细胞发生肿瘤消退。我们的结果支持RHOB/AKT信号在对EGFR-TKI耐药中的作用，并提出RHOB作为患者对EGFR-TKI治疗反应的潜在预测指标。
