RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade.
RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade.
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DOI：
10.1158/1535-7163.mct-17-0464
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发表时间：
2018-07
影响因子：
5.7
通讯作者：
Bass AJ
中科院分区：
文献类型：
--
作者：
Bockorny B;Rusan M;Chen W;Liao RG;Li Y;Piccioni F;Wang J;Tan L;Thorner AR;Li T;Zhang Y;Miao C;Ovesen T;Shapiro GI;Kwiatkowski DJ;Gray NS;Meyerson M;Hammerman PS;Bass AJ
成纤维细胞生长因子受体（FGFR）激酶是多种癌症类型（包括肺癌和头颈部鳞状细胞癌、胆管癌和膀胱癌）中有希望的治疗靶点。尽管几种FGFR激酶抑制剂已进入临床试验，但单药临床疗效不高，并且总是发生耐药。因此，我们进行了全基因组功能筛选，以表征在FGFR 1依赖性肺癌细胞模型中对FGFR抑制的抗性机制。我们的筛选鉴定了已知的耐药驱动因子，如MET，以及其他新型耐药介质，包括神经营养因子受体途径（NTRKs）、TAM酪氨酸激酶家族（TYRO 3、MERTK、AXL）和MAPK途径的成员，这些在其他FGFR依赖性模型中得到了进一步验证。在正交方法中，我们通过在FGFR 1和FGFR 3依赖性细胞模型中长期暴露于FGFR抑制剂产生了一大组耐药克隆，并采用L1000平台表征了基因表达谱。值得注意的是，抗性克隆富集NTRK和MAPK信号通路。发现对FGFR抑制的抗性的新介质部分地通过MAPK途径的再活化来补偿FGFR损失。有趣的是，在我们的筛选中鉴定的FGFR和特异性受体酪氨酸激酶的共抑制不足以抑制ERK活性或防止对FGFR抑制的抗性，表明RAS-MAPK途径的冗余再激活。然而，FGFR和MEK的双重阻断被证明是预防不同FGFR依赖性耐药的更有力的方法，并且可能代表在FGFR依赖性癌症中实现对FGFR抑制的持久应答的治疗机会。
The Fibroblast Growth Factor Receptor (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 (NTRKs), 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, co-inhibition 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 re-activation 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.