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RAS-MAPK reactivation facilitates acquired resistance in FGFR1-amplified lung cancer and underlies a rationale for upfront FGFR-MEK blockade
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-04-13 , DOI: 10.1158/1535-7163.mct-17-0464
Bruno Bockorny 1, 2, 3 , Maria Rusan 1, 3, 4 , Wankun Chen 5, 6 , Rachel G. Liao 3 , Yvonne Li 1, 3 , Federica Piccioni 7 , Jun Wang 8 , Li Tan 9, 10 , Aaron R. Thorner 1, 11 , Tianxia Li 1 , Yanxi Zhang 1 , Changhong Miao 5, 6 , Therese Ovesen 4 , Geoffrey I. Shapiro 1 , David J. Kwiatkowski 1 , Nathanael S. Gray 10, 12 , Matthew Meyerson 1, 3 , Peter S. Hammerman 1, 3 , Adam J. Bass 1, 3
Affiliation  

The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1-dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS–MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526–39. ©2018 AACR.

中文翻译:

RAS-MAPK 再激活促进 FGFR1 扩增肺癌的获得性耐药,并为预先阻断 FGFR-MEK 提供了依据

FGFR 激酶是多种癌症类型的有希望的治疗靶点,包括肺癌和头颈部鳞状细胞癌、胆管癌和膀胱癌。尽管有几种 FGFR 激酶抑制剂已进入临床试验,但单药临床疗效一般,耐药性始终存在。因此,我们进行了全基因组功能筛选,以表征 FGFR1 依赖性肺癌细胞模型中对 FGFR 抑制的抗性机制。我们的筛选确定了已知的耐药性驱动因素,例如 MET,以及其他新的耐药性介质,包括神经营养因子受体通路 (NTRK)、酪氨酸激酶 TAM 家族(TYRO3、MERTK、AXL)和 MAPK 通路的成员,并在额外的 FGFR 依赖模型。在正交方法中,我们通过在 FGFR1 和 FGFR3 依赖性细胞模型中长期暴露于 FGFR 抑制剂产生了大量抗性克隆,并使用 L1000 平台表征了基因表达谱。值得注意的是,抗性克隆富集了 NTRK 和 MAPK 信号通路。发现对 FGFR 抑制具有抗性的新型介质可部分通过 MAPK 途径的重新激活来补偿 FGFR 的损失。有趣的是,在我们的筛选中发现的 FGFR 和特定受体酪氨酸激酶的共同抑制不足以抑制 ERK 活性或防止对 FGFR 抑制的抗性,这表明 RAS-MAPK 途径的重复激活。然而,FGFR 和 MEK 的双重封锁,被证明是一种更有效的方法,可以预防不同 FGFR 依赖性之间的耐药性,并且可能代表在 FGFR 依赖性癌症中实现对 FGFR 抑制的持久反应的治疗机会。摩尔癌症治疗; 17(7); 1526-39。©2018 AACR。
更新日期:2018-04-13
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