Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro. This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572–85. ©2017 AACR.

中文翻译：

---

对 osimertinib 和 JNJ-61186372（一种 EGFR/Met 双特异性抗体）体内耐药性的表征揭示了独特且一致的耐药机制

美国大约 10% 的非小细胞肺癌 (NSCLC) 患者和亚洲 40% 的 NSCLC 患者具有激活的表皮生长因子受体 (EGFR) 突变，并且有资格接受靶向抗 EGFR 治疗。尽管与这种治疗相关的预期寿命延长，但对 EGFR 酪氨酸激酶抑制剂和抗 EGFR 抗体的耐药性几乎是不可避免的。为了确定可以共同靶向以克服耐药性的其他信号通路，我们量化了控制耐药性癌细胞生长和存活的肿瘤特异性分子变化。基于质谱的定量蛋白质组学被用于分析来自四种异种移植非小细胞肺癌模型的 41 种耐药肿瘤的体内信号传导变化。我们在对不可逆第三代 EGFR 抑制剂奥希替尼或新型双靶向 EGFR/Met 抗体 JNJ-61186372 治疗耐药的肿瘤中发现了独特且肿瘤特异性的酪氨酸磷酸化重新布线。观察到来自 EGFR 家族成员、Shc1 和 Gab1 或 Src 家族激酶 (SFK) 底物的酪氨酸磷酸化肽的肿瘤特异性增加，强调了肿瘤独特地逃避 EGFR 抑制的不同能力。尽管每个治疗组中的大多数耐药肿瘤都显示出对 EGFR 和 SFK 信号的显着抑制，但 EGFR 抑制（奥希替尼）和 SFK 抑制（萨拉卡替尼或达沙替尼）的组合导致体外细胞生长进一步下降。这一结果表明，残留的 SFK 信号介导了治疗耐药性，而通过联合治疗消除该信号可能会延迟耐药性的发生。总体而言，对个体耐药性肿瘤的分析捕获了独特的体内信号重新布线，而这可能会被体外细胞群平均值的分析所掩盖。摩尔癌症治疗; 16(11); 2572-85。©2017 AACR。