MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.
MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.
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DOI：
10.1371/journal.pone.0170798
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Santis G
中科院分区：
文献类型：
--
作者：
Ortiz-Zapater E;Lee RW;Owen W;Weitsman G;Fruhwirth G;Dunn RG;Neat MJ;McCaughan F;Parker P;Ng T;Santis G
晚期肺癌的存活率很低，治疗方法很少。EGFR酪氨酸激酶抑制剂(TKI)对激活EGFR突变的患者有很高的应答率，但获得性耐药是不可避免的。获得EGFR T790M突变导致50%以上的耐药性；MET扩增也很常见。临床前数据表明MET和EGFR抑制剂之间存在协同作用。我们假设，EGFR-MET二聚化决定了对MET抑制的反应，这取决于EGFR突变状态，与MET拷贝数无关。我们从NCI-H1975细胞中建立了共表达L858R和T790M EGFR突变的等基因细胞系，即H1975L858R/T790M(EGFR TKI抗性)、H1975L858R(致敏)和H1975WT(野生型)，以验证这一假设。我们通过Förster共振能量转移(FRET)评估了Met TKI(SGX523)诱导的异种移植模型中的细胞增殖和肿瘤生长/间质形成，并与EGFR-MET二聚化相关。SGX523显著抑制H1975L858R/T790M细胞的增殖和移植瘤的生长，并降低ERK的磷酸化。在H1975L858R和H1975WT细胞中未见相同的表达。SGX523仅减少H1975L858R的间质形成。SGX523抑制H1975L858R/T790M的EGFR-MET二聚化，但诱导H1975L858R形成二聚体，而对H1975WT无影响。我们的数据表明，SGX523和EGFR-MET异源二聚体对MET的抑制是由EGFR基因决定的。由于肿瘤的行为受到这种相互作用的调节，这可能决定治疗效果。
Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy.