壹生资讯-EGFR 驱动的肺癌生长和体内治疗反应的遗传决定因素（Cancer Discovery）

您已通过HCP身份认证和信息审核

(

EGFR 驱动的肺癌生长和体内治疗反应的遗传决定因素（Cancer Discovery）

2021-07-18作者：论坛报芊蔚资讯

支持护理和治疗的相关问题非原创

SCI速递

2021

_{Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo}

Giorgia F, Chuan L, Hongchen C, Jessica H, Wen-Yang L, Deborah A, Katherine H, Jungmin C, Anna W, Laura A, Dylan M, Nicholas R, Stellar L Robert H, Scott G, Maximilian D, Heather W, Dmitri P, Monte W, and Katerina P. Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

Abstract 摘要

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2—the strongest drivers of growth in a KRAS-driven model—reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment.

在肺腺癌中，致癌 EGFR 突变与许多抑癌基因改变同时发生；然而，这些突变在肿瘤生长和体内治疗的反应的重要程度依然未知。

在EGFR驱动的Trp53缺陷型肺腺癌小鼠模型中，通过对10个推定的肿瘤抑制基因失活影响的量化，我们发现Apc、Rb1 或 Rbm10 的失活强烈促进了肿瘤生长。

始料未及的是，在KRAS驱动模型中最强大的驱动基因Lkb1和Setd2的失活减少了EGFR所驱动的肿瘤增长。

以上结果与人类EGFR驱动肺腺癌和KRAS驱动肺腺癌中的突变频率一致。

此外，KEAP1 的失活导致 EGFR 驱动的肿瘤对 EGFR 抑制剂奥希替尼的敏感性降低，并且 KEAP1 通路中的基因突变与患者接受酪氨酸激酶抑制剂治疗的时间的减少有关。

研究强调，在不同的致癌因素背景下基因改变的影响不同，以及适应的情况随治疗方式而改变。

Significance 重要性

By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.

通过体内复杂基因突变建模，这项研究揭示了限制 EGFR 突变肿瘤生长的关键肿瘤抑制基因。此外，我们发现 KEAP1失活降低了肿瘤对酪氨酸激酶抑制剂的敏感性。因此，我们的方法确定了肺腺癌中具有重要的生物学和治疗意义的基因突变。

来源：SCI天天读

微信图片_20200824111328.jpg

200 评论

知情同意书

EGFR 驱动的肺癌生长和体内治疗反应的遗传决定因素（Cancer Discovery）

热门资讯

关于我们

中国医学论坛报微信矩阵

助力乡村振兴帮扶行动

友情链接