Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression
Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression
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致癌性 ERBB2 畸变和 KRAS 突变共同促进胰腺导管腺癌进展
DOI：
10.1093/carcin/bgz086
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发表时间：
2020-01-01
期刊：
影响因子：
4.7
通讯作者：
Wang, Yuexiang
中科院分区：
文献类型：
--
作者：
Li, Zhang;Shao, Chenghao;Wang, Yuexiang
胰腺导管腺癌（PDAC）是一种毁灭性的疾病，治疗方法很少，是肿瘤学领域的巨大挑战之一。激活KRAS突变，发生在>90%的PDAC中，存在于胰腺上皮内瘤变病变中，PDAC的前体导管病变，表明额外的遗传改变有助于PDAC的发病机制。PDAC测序项目在8.5%的PDAC患者中发现了复发性基因组ERBB2改变、突变和扩增，在100个受体酪氨酸激酶编码基因中排名第一。将编码蛋白变体S310F、S423R、R678Q、Q679L、E717D、L755S、V777L和V842I的ERBB2突变引入人胰腺上皮细胞可引起致癌转化，增加ERBB2信号传导、裸小鼠锚定非依赖性细胞生长和肿瘤异种移植物生长，表明它们是激活突变。有趣的是，在许多pdac中，ERBB2和KRAS突变同时发生。ERBB2激活突变体促进kras驱动的致癌特性。将ERBB2突变引入KRAS突变的PDAC细胞，激活ERBB2信号，促进肿瘤生长，减弱KRAS依赖性。相比之下，在ERBB2扩增的PDAC细胞中，crispr介导的ERBB2敲除（KO）抑制ERBB2信号传导、集落形成、非锚定生长和肿瘤异种移植物形成。最后，用小分子抑制剂治疗可以消除致癌ERBB2畸变。ERBB2和KRAS抑制在体外共同抑制PDAC细胞生长并促进裸鼠肿瘤消退，为在目前无法治疗的ERBB2突变PDAC患者中测试抗ERBB2药物与KRAS抑制剂联合使用提供了理论依据。
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with few therapeutic options, representing one of the great challenges in oncology. Activating KRAS mutation, occurring in >90% PDACs, is present in pancreatic intraepithelial neoplasia lesions, the precursor ductal lesions of PDAC, indicating additional genetic alterations contribute to the pathogenesis of PDAC. PDAC sequencing projects identify recurrent genomic ERBB2 alterations, mutations and amplifications, in 8.5% of PDAC patients, ranking as the top hit among the 100 receptor tyrosine kinases-encoding genes. Introduction of the ERBB2 mutations encoding protein variants S310F, S423R, R678Q Q679L, E717D, L755S,V777L and V842I into human pancreatic epithelial cells causes oncogenic transformation, increasing ERBB2 signaling, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. Interestingly, in many PDACs, mutations in ERBB2 and KRAS occur together. ERBB2 activating mutants facilitate KRAS-driven oncogenic properties. Introduction of ERBB2 mutations into KRAS-mutant PDAC cells activates ERBB2 signaling, promotes tumor growth and attenuates KRAS dependency. In contrast, a CRISPR-mediated knockout (KO) of ERBB2 in ERBB2-amplified PDAC cells inhibits ERBB2 signaling, colony formation, anchorage-independent growth and tumor xenograft formation. Finally, oncogenic ERBB2 aberrations can be abrogated by treatment with small-molecule inhibitors. ERBB2 and KRAS inhibition cooperate to suppress PDAC cell growth in vitro and to promote tumor regression in nude mice, providing a rationale for testing an anti-ERBB2 drug in combination with a KRAS inhibitor in ERBB2-mutant PDAC patients that are currently untreatable.