Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.
Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.
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双ALK和EGFR抑制靶向ALK重排的肺癌中获得对酪氨酸激酶抑制剂Crizotinib的获得性机制。
DOI：
10.1016/j.lungcan.2013.09.019
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Costa DB
中科院分区：
文献类型：
--
作者：
Yamaguchi N;Lucena-Araujo AR;Nakayama S;de Figueiredo-Pontes LL;Gonzalez DA;Yasuda H;Kobayashi S;Costa DB
多靶点酪氨酸激酶抑制剂 (TKI) 克唑替尼 (crizotinib) 对 ALK 易位非小细胞肺癌 (NSCLC) 具有活性；然而，随着时间的推移，获得性抵抗总是会产生。此前仅三分之一的耐药肿瘤涉及 ALK 突变。我们试图评估替代的耐药机制和临床前策略，以在 EML4-ALK 驱动的细胞系中克服这些机制。我们选择了 NSCLC 细胞系 NCI-H3122（H3122：EML4-ALK E13；A20）和衍生的耐药变体，它们能够在 1μM 克唑替尼存在下生长。对这些样本进行 ALK 突变、克唑替尼与其他 TKI 联合用药的敏感性以及替代酪氨酸激酶的激活分析。所有 H3122 克唑替尼耐药 (CR) 克隆均缺乏 ALK 激酶结构域的扩增或突变。为了评估是否有可能的替代激酶在这些耐药细胞中充当下游信号激活的“旁路”轨道，我们对磷酸受体酪氨酸激酶阵列进行了研究，结果证明 CR 克隆在接触克唑替尼之前和之后比 H3122 细胞具有更高的磷酸化 EGFR 信号。使用双 ALK TKI（与克唑替尼）与组合 TKI 抑制的功能方法作为可能靶点的二次筛选。克唑替尼 + 厄洛替尼（可逆 EGFR TKI）和克唑替尼 + 阿法替尼（不可逆 EGFR/ERBB2 TKI）能够抑制 H3122 CR 克隆的生长，证实 EGFR 激活是一种耐药机制。从培养基中去除克唑替尼使 CR 细胞对克唑替尼重新敏感。我们确定 EGFR 的激活是 ALK 易位 NSCLC 临床前模型中克唑替尼耐药的机制。如果 EGFR 激活被证实是 ALK TKI 诱导患者源性肿瘤耐药的主要机制，则可以探索在这一重要的 NSCLC 队列中使用 ALK 加 EGFR TKI。
The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK. We selected the NSCLC cell line NCI-H3122 (H3122: EML4-ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination to other TKIs, and for activation of alternative tyrosine kinases. All H3122 crizotinib resistant (CR) clones lacked amplification or mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as “bypass” tracks for downstream signaling activation in these resistance cells, we performed of phosho-receptor tyrosine kinase array that demonstrated that CR clones had higher phospho-EGFR signals than H3122 cells before and after exposure to crizotinib. A functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition was used as a secondary screen for possible targets. Crizotinib + erlotinib (reversible EGFR TKI) and crizotinib + afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, confirming EGFR activation as a mechanism of resistance. The removal of crizotinib from the culture media re-sensitized CR cells to crizotinib. We identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of ALK TKI-induced resistance in patient-derived tumors, the use of ALK plus EGFR TKIs could be explored for this important cohort of NSCLCs.
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影响因子：
11.2
作者：
Sasaki T;Koivunen J;Ogino A;Yanagita M;Nikiforow S;Zheng W;Lathan C;Marcoux JP;Du J;Okuda K;Capelletti M;Shimamura T;Ercan D;Stumpfova M;Xiao Y;Weremowicz S;Butaney M;Heon S;Wilner K;Christensen JG;Eck MJ;Wong KK;Lindeman N;Gray NS;Rodig SJ;Jänne PA
通讯作者：
Jänne PA
DOI：
10.1038/nrclinonc.2012.43
发表时间：
2012-04-03
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
影响因子：
254.7
作者：
Siegel, Rebecca;Naishadham, Deepa;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
20.4
作者：
Costa, Daniel B.;Kobayashi, Susumu
通讯作者：
Kobayashi, Susumu
影响因子：
64.8
作者：
Weir, Barbara A.;Woo, Michele S.;Meyerson, Matthew
通讯作者：
Meyerson, Matthew