Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations
Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations
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DOI：
10.1016/j.jtho.2020.01.027
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发表时间：
2020-05-01
影响因子：
20.4
通讯作者：
Cortot, Alexis B.
中科院分区：
文献类型：
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作者：
Jamme, Philippe;Fernandes, Marie;Cortot, Alexis B.
已发现肝细胞生长因子受体（MET）酪氨酸激酶抑制剂（MET TKI）对伴有MET外显子14跳读突变（METex 14突变）的晚期NSCLC有效，但原发性耐药似乎很常见，因为缓解率低于其他癌基因成瘾NSCLC的靶向TKI。鉴于MET和磷酸肌醇3-激酶（PI 3 K）之间已知的相互作用，我们假设在METex 14 NSCLC中，PI 3 K通路的改变可能导致MET TKI的原发性耐药。我们回顾了65例METex 14 NSCLC患者的临床资料，通过靶向下一代测序（突变）和免疫组化（磷酸酶和张力蛋白同源物[PTEN]的缺失）评估PI 3 K通路的改变。我们使用来自对MET TKI原发性耐药患者的细胞系和携带aMETex 14突变和PI 3 K通路改变的细胞系，评估了对MET TKI单独使用或与PI 3 K抑制剂联合使用的敏感性，并研究了相关信号通路。我们在65个样本中的2个（3%）中发现了磷脂酰肌醇3-激酶催化亚基α（PIK 3CA）突变，在26个样本中的6个（23%）中发现了PTEN缺失。所有三名MET TKI治疗的PI 3 K通路改变的患者在首次评估时均发现疾病进展。同样，MET TKI对具有PI 3 K通路改变的METex 14突变细胞系的增殖没有影响，包括缺乏PTEN的患者来源的细胞系。MET TKI与PI 3 K抑制剂联合治疗可抑制PI 3 K和MAPK信号传导，并恢复对MET TKI的敏感性。PI 3 K通路改变在METex 14 NSCLC中很常见，可能导致MET TKI的原发性耐药。在临床前模型中，PI 3 K抑制可恢复对MET TKI的敏感性。
Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that inMETex14NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients withMETex14NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both aMETex14mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI–treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation ofMETex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common inMETex14NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.