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：

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对奥西替尼和EGFR / Met双特异性抗体JNJ-61186372的体内耐药性揭示了独特的耐药性共识机制

在美国，约10％的非小细胞肺癌（NSCLC）患者和亚洲的40％的NSCLC患者具有激活的表皮生长因子受体（EGFR）突变，并有资格接受靶向抗EGFR治疗。尽管延长了与这种治疗有关的预期寿命，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克服耐药性的其他信号传导途径，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描述来自四种异种移植NSCLC模型的41种对治疗有抵抗力的肿瘤的体内信号变化。我们在对不可逆的第三代EGFR抑制剂osimertinib或新型双重靶向EGFR / Met抗体JNJ-61186372产生抗药性的肿瘤中发现了独特且特定于肿瘤的酪氨酸磷酸化重新连接。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抑制的能力。尽管每个治疗组中的大多数耐药肿瘤均表现出对EGFR和SFK信号的显着抑制作用，但EGFR抑制作用（osimertinib）和SFK抑制作用（saracatinib或dasatinib）的组合导致体外细胞生长进一步降低。该结果表明，残余的SFK信号传导介导了治疗抗性，并且通过联合疗法消除该信号可能延迟抗性的发作。总的来说，对单个抗药性肿瘤的分析捕获了独特的体内信号转导，这可能被体外细胞群体平均值的分析所掩盖。分子癌疗法；16（11）; 2572–85。©2017 AACR。