Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.
Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.
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DOI：
10.1158/2159-8290.cd-11-0046
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发表时间：
2011-12
期刊：
影响因子：
28.2
通讯作者：
Hahn WC
中科院分区：
文献类型：
--
作者：
Cheung HW;Du J;Boehm JS;He F;Weir BA;Wang X;Butaney M;Sequist LV;Luo B;Engelman JA;Root DE;Meyerson M;Golub TR;Jänne PA;Hahn WC
我们之前在原发性肺腺癌的一个子集中确定了染色体 22q11.21 上的一个反复扩增区域。在这里，我们展示了编码接头蛋白的 CRKL 在具有 22q11.21 扩增的非小细胞肺癌 (NSCLC) 细胞中扩增并过度表达。 CRKL 在永生化人气道上皮细胞中的过度表达促进贴壁独立生长和致瘤性。致癌 CRKL 激活 SOS1-RAS-RAF-ERK 和 SRC-C3G-RAP1 通路。在含有 CRKL 扩增的 NSCLC 细胞中抑制 CRKL 会诱导细胞死亡。 EGFR 突变细胞中 CRKL 的过度表达通过激活 ERK 和 AKT 信号传导诱导对吉非替尼的耐药性。我们在 EGFR 抑制剂治疗的肺腺癌中发现了在治疗前不存在的 CRKL 扩增。这些观察结果表明 CRKL 过表达诱导细胞转化，证明 CRKL 作为 NSCLC 子集的治疗靶点，其中包含 CRKL 扩增，并暗示 CRKL 是对 EGFR 导向治疗产生耐药性的另一种机制。
We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage independent growth and tumorigenicity. Oncogenic CRKL activates SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in EGFR mutant cells induces resistance to gefitinib by activating ERK and AKT signaling. We identified CRKL amplification in an EGFR inhibitor treated lung adenocarcinoma that was not present prior to treatment. These observations show that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.