Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.
Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.
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DOI：
10.1038/s41467-022-33210-2
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发表时间：
2022-09-24
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
基于 DNA 的下一代测序检测到的基因融合作为 EGFR 突变非小细胞肺癌中 EGFR 酪氨酸激酶抑制剂的耐药机制，其临床意义仍不清楚。通过研究接受 EGFR 抑制剂和针对假定的耐药性融合癌基因的药物联合治疗的 EGFR 抑制剂耐药患者，我们确定了从这种治疗方法中受益和不受益的患者。通过对 504 名 EGFR 突变型肺癌患者的潜在耐药性融合癌基因进行 RNA-seq 评估，我们发现其中只有少数具有功能性，可能能够赋予 EGFR 抑制剂耐药性。我们使用基于 CRISPR 的 EGFR 突变细胞系编辑进一步在体外功能验证融合癌基因，并使用这些模型来识别联合疗法的已知和未知耐药机制。总的来说，我们的结果部分揭示了融合癌基因作为潜在耐药机制的复杂性质，并强调了可用于确定其功能意义的方法。融合基因已被提议作为肺癌中 EGFR 酪氨酸激酶抑制剂 (TKI) 耐药的潜在机制。在此，作者鉴定了与非小细胞肺癌中 EGFR TKI 耐药相关的基因融合，并测试了这些融合如何影响体外对 EGFR TKI 的反应。
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance. Fusion genes have been proposed as a potential mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Here, the authors identify gene fusions that are associated with resistance to EGFR TKIs in non-small cell lung cancers, and test how these fusions impact the response to EGFR TKIs in vitro.
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DOI：
10.1056/nejmoa2005653
发表时间：
2020-08-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Drilon A;Oxnard GR;Tan DSW;Loong HHF;Johnson M;Gainor J;McCoach CE;Gautschi O;Besse B;Cho BC;Peled N;Weiss J;Kim YJ;Ohe Y;Nishio M;Park K;Patel J;Seto T;Sakamoto T;Rosen E;Shah MH;Barlesi F;Cassier PA;Bazhenova L;De Braud F;Garralda E;Velcheti V;Satouchi M;Ohashi K;Pennell NA;Reckamp KL;Dy GK;Wolf J;Solomon B;Falchook G;Ebata K;Nguyen M;Nair B;Zhu EY;Yang L;Huang X;Olek E;Rothenberg SM;Goto K;Subbiah V
通讯作者：
Subbiah V
影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
影响因子：
--
作者：
Gainor JF;Gadgeel S;Ou SI;Yeap B;Otterson GA;Shaw AT
通讯作者：
Shaw AT
影响因子：
3.2
作者：
Ferguson, Sherise D.;Zhou, Shouhao;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
影响因子：
158.5
作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
通讯作者：
Ranson, Malcolm