Cargnelutti Marilisa, Corso Simona, Pergolizzi Margherita, Mévellec Laurence, Aisner Dara L, Dziadziuszko Rafal, Varella-Garcia Marileila, Comoglio Paolo M, Doebele Robert C, Vialard Jorge, Giordano Silvia
Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy.
Department of Oncology, University of Torino, Italy.
Oncotarget. 2015 Mar 10;6(7):5182-94. doi: 10.18632/oncotarget.3311.
The ROS1 tyrosine kinase is activated in lung cancer as a consequence of chromosomal rearrangement. Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement. We found that activation of the RAS pathway in the HCC78 cell model, due to either KRAS/NRAS mutations or to KRAS amplification, rendered the cells resistant to ROS1 inhibition. These cells were cross-resistant to different ROS1 inhibitors, but sensitive to inhibitors of the RAS signaling pathway. Interestingly, we identified focal KRAS amplification in a biopsy of a tumor from a patient that had become resistant to crizotinib treatment.Altogether our data suggest that the activation of members of the RAS family can confer resistance to ROS1 inhibitors. This has important clinical implications as: (i) RAS genetic alterations in ROS1+ primary tumors are likely negative predictors of efficacy for targeted drugs and (ii) this kind of resistance is unlikely to be overcome by the use of more specific or more potent ROS1 targeting drugs.
由于染色体重排，ROS1酪氨酸激酶在肺癌中被激活。尽管在用激酶抑制剂克唑替尼治疗的携带重排ROS1肿瘤（ROS1+）的肺癌患者中观察到了高缓解率和疾病控制，但这些患者中的许多最终还是复发了。为了确定对ROS1抑制剂耐药的机制，我们从携带SLC34A2-ROS1重排的HCC78肺癌细胞中生成了耐药细胞。我们发现，在HCC78细胞模型中，由于KRAS/NRAS突变或KRAS扩增导致的RAS途径激活，使细胞对ROS1抑制产生耐药性。这些细胞对不同的ROS1抑制剂具有交叉耐药性，但对RAS信号通路抑制剂敏感。有趣的是，我们在一名对克唑替尼治疗产生耐药性的患者的肿瘤活检中发现了局灶性KRAS扩增。总之，我们的数据表明，RAS家族成员的激活可以赋予对ROS1抑制剂的耐药性。这具有重要的临床意义，因为：（i）ROS1+原发性肿瘤中的RAS基因改变可能是靶向药物疗效的阴性预测指标，（ii）这种耐药性不太可能通过使用更特异或更强效的ROS1靶向药物来克服。
