INTRODUCTION MET TKIs (tyrosine kinase inhibitors) have demonstrated efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than for targeted TKIs of other oncogene-addicted NSCLC. Given the known interplay between MET and PI3K, we hypothesized that in METex14 NSCLC, PI3K-pathway alterations might contribute to primary resistance to MET TKIs. METHODS We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K-pathway alterations by targeted NGS (mutations) and immunohistochemistry (loss of PTEN). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K-pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. RESULTS We found a PIK3CA mutation in 2/65 samples (3%) and loss of PTEN in 6/26 (23%). All three of the MET-TKI-treated patients with a PI3K pathway alteration had shown progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-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. CONCLUSION PI3K-pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.

中文翻译：

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PI3K 通路的改变导致携带 MET 外显子 14 跳跃突变的非小细胞肺癌对 MET 抑制剂产生抗性

简介 MET TKI（酪氨酸激酶抑制剂）已证明对具有导致 MET 外显子 14 跳跃（METex14 突变）的突变的晚期 NSCLC 有效，但原发性耐药似乎很常见，因为响应率低于其他致癌基因成瘾的 NSCLC 的靶向 TKI。鉴于 MET 和 PI3K 之间已知的相互作用，我们假设在 METex14 NSCLC 中，PI3K 通路的改变可能导致对 MET TKI 的原发性耐药。方法我们回顾了 65 名 METex14 NSCLC 患者的临床数据，通过靶向 NGS（突变）和免疫组织化学（PTEN 缺失）评估 PI3K 通路的改变。使用源自对 MET TKI 具有原发性耐药性的患者的细胞系和具有 METex14 突变和 PI3K 通路改变的细胞系，我们评估了对单独使用或与 PI3K 抑制剂一起使用的 MET TKI 的敏感性，并研究了相关的信号通路。结果 我们在 2/65 样本 (3%) 中发现了 PIK3CA 突变，在 6/26 (23%) 中发现了 PTEN 缺失。所有三名接受 MET-TKI 治疗的 PI3K 通路改变的患者在第一次评估时都显示出疾病进展。同样，MET TKI 对具有 PI3K 通路改变的 METex14 突变细胞系的增殖没有影响，包括缺乏 PTEN 的患者来源细胞系。将 MET TKI 与 PI3K 抑制剂联合治疗会抑制 PI3K 和 MAPK 信号传导并恢复对 MET TKI 的敏感性。结论 PI3K 通路改变在 METex14 NSCLC 中很常见，可能会导致对 MET TKI 的原发性耐药。在临床前模型中，PI3K 抑制可恢复对 MET TKI 的敏感性。