Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).
Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).
复制标题
DOI：
10.1093/annonc/mdx396
复制
发表时间：
2017-10-01
期刊：
影响因子：
--
通讯作者：
Vivancos A
中科院分区：
文献类型：
--
作者：
Martinez-Marti A;Felip E;Matito J;Mereu E;Navarro A;Cedrés S;Pardo N;Martinez de Castro A;Remon J;Miquel JM;Guillaumet-Adkins A;Nadal E;Rodriguez-Esteban G;Arqués O;Fasani R;Nuciforo P;Heyn H;Villanueva A;Palmer HG;Vivancos A
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）如奥希替尼是携带T790 M的转移性非小细胞肺癌（NSCLC）EGFR突变体的最后一种靶向治疗药物。已经提出了对第三代EGFR-TKI的获得性耐药的不同机制。因此，确定新的有效战略以克服连续获得的抗性机制至关重要。对于Amplicon-seq分析，使用来自索引患者（不同时间点的原发性和转移性病变）的样品以及对应于不同治疗组的患者来源的原位异种移植肿瘤。所有样本均由病理学家进行福尔马林固定石蜡包埋、选择和评价。对于液滴数字PCR，选择了20例在基线时诊断为NSCLC或进展至不同TKI治疗线的患者。福尔马林固定石蜡包埋块对应于原发肿瘤或转移标本用于分析。对于单细胞分析，从无胸腺nu/nu小鼠的脑中解剖原位生长的转移瘤，并在-80 °C下冷冻保存。在一例EGFR T790 M突变的NSCLC患者的脑转移病灶中，我们在奥希替尼长期治疗后检测到MET基因扩增。重要的是，capmatinib（c-MET抑制剂）和阿法替尼（ErbB-1/2/4抑制剂）联合使用完全抑制了原位注射该脑转移瘤细胞的小鼠的肿瘤生长。在接受capmatinib或afatinib单药治疗的小鼠中，我们观察到KRAS G12 C克隆的出现。单细胞基因表达分析也揭示了肿瘤内的异质性，表明存在KRAS驱动的亚克隆。我们还在接受各种EGFR-TKI治疗的患者中检测到低频KRAS G12 C等位基因。EGFR突变型肺癌患者对后续EGFR-TKI治疗系的获得性耐药可能诱导遗传可塑性。我们评估了具有获得性MET扩增的奥西替尼耐药肿瘤中肿瘤异质性的生物学见解，并提出了这种情况下的新治疗策略。
Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at −80°C. In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.
登录
查看更多内容
DOI：
10.1126/science.1247651
发表时间：
2014-02-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaitin DA;Kenigsberg E;Keren-Shaul H;Elefant N;Paul F;Zaretsky I;Mildner A;Cohen N;Jung S;Tanay A;Amit I
通讯作者：
Amit I
影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
11.2
作者：
Eberlein CA;Stetson D;Markovets AA;Al-Kadhimi KJ;Lai Z;Fisher PR;Meador CB;Spitzler P;Ichihara E;Ross SJ;Ahdesmaki MJ;Ahmed A;Ratcliffe LE;O'Brien EL;Barnes CH;Brown H;Smith PD;Dry JR;Beran G;Thress KS;Dougherty B;Pao W;Cross DA
通讯作者：
Cross DA
影响因子：
158.5
作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
通讯作者：
Ranson, Malcolm
影响因子：
11.2
作者：
Jia, Yong;Juarez, Jose;Kasibhatla, Shailaja
通讯作者：
Kasibhatla, Shailaja