Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-19-1667
复制
发表时间：
2020-01-15
影响因子：
11.5
通讯作者：
Blakely, Collin M.
中科院分区：
文献类型：
--
作者：
Rotow, Julia K.;Gui, Philippe;Blakely, Collin M.
目的：虽然携带MET外显子14跳跃突变(METEX 14)的晚期非小细胞肺癌(NSCLC)患者经常受益于MET酪氨酸激酶抑制剂(TKI)治疗，但临床疗效受到原发耐药和获得性耐药的限制。这种耐药性的分子基础尚不完全清楚。实验设计：对289例晚期非小细胞肺癌患者的无细胞循环肿瘤DNA进行靶向测序分析。结果：与Eger突变的非小细胞肺癌相比，在非小细胞肺癌中检测到显著的共生Ras-Mark通路基因改变(例如，在KRAS，NE1)。MET-TKI治疗反应降低与Ras-MAPK通路共现改变之间存在关联。在一个表达典型METEX 14突变的临床前模型中，KRAS过度表达或NE1下调激活了MAPK信号，以促进ME TKI耐药。这种耐药性通过与克里佐替尼和MEK抑制剂曲美替尼的共同治疗而被克服。结论：我们的研究提供了晚期METEX 14突变的NSCLC的共生改变的基因组图谱，并建议了一种潜在的针对MAPK信号转导的联合治疗策略，以提高临床疗效。
Purpose: Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Experimental Design: Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.Results: Prominent co-occurring RAS-MARK pathway gene alterations (e.g., in KRAS, NE1) were detected in NSCLCs with METex14 skipping alterations as compared with EGER-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NE1 downregulation hyperactivatedMAPK signaling to promote ME TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.Conclusions: Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.