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Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.ccell.2019.12.013 Dhivya R Sudhan 1 , Angel Guerrero-Zotano 2 , Helen Won 3 , Paula González Ericsson 4 , Alberto Servetto 1 , Mariela Huerta-Rosario 1 , Dan Ye 1 , Kyung-Min Lee 1 , Luigi Formisano 2 , Yan Guo 5 , Qi Liu 6 , Lisa N Kinch 7 , Monica Red Brewer 2 , Teresa Dugger 2 , James Koch 2 , Michael J Wick 8 , Richard E Cutler 9 , Alshad S Lalani 9 , Richard Bryce 9 , Alan Auerbach 9 , Ariella B Hanker 10 , Carlos L Arteaga 10
Cancer Cell ( IF 48.8 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.ccell.2019.12.013 Dhivya R Sudhan 1 , Angel Guerrero-Zotano 2 , Helen Won 3 , Paula González Ericsson 4 , Alberto Servetto 1 , Mariela Huerta-Rosario 1 , Dan Ye 1 , Kyung-Min Lee 1 , Luigi Formisano 2 , Yan Guo 5 , Qi Liu 6 , Lisa N Kinch 7 , Monica Red Brewer 2 , Teresa Dugger 2 , James Koch 2 , Michael J Wick 8 , Richard E Cutler 9 , Alshad S Lalani 9 , Richard Bryce 9 , Alan Auerbach 9 , Ariella B Hanker 10 , Carlos L Arteaga 10
Affiliation
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We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.
中文翻译：
TORC1的过度活化会导致对HER2突变型癌症中的Pan-HER酪氨酸激酶抑制剂Neratinib的耐药性。
我们通过逐步增加剂量开发耐那拉替尼的HER2突变癌细胞。RNA测序确定TORC1信号传导是耐药性的一种可行机制。HER2突变乳腺癌患者患者异种移植物（PDXs）中的原发性和获得性neratinib耐药性也与TORC1过度活跃有关。基因抑制RAPTOR或RHEB消融了P-S6，恢复了对酪氨酸激酶抑制剂的敏感性。TORC1抑制剂依维莫司和neratinib的组合有效抑制了耐neratinib的异种移植物和从耐neratinib的PDX建立的类器官的生长。RNA和全外显子组测序揭示了耐纳替尼耐药模型子集中的RAS介导的TORC1激活。临床上对那拉替尼耐药的HER2突变肿瘤的DNA测序
更新日期：2020-01-23
中文翻译：
TORC1的过度活化会导致对HER2突变型癌症中的Pan-HER酪氨酸激酶抑制剂Neratinib的耐药性。
我们通过逐步增加剂量开发耐那拉替尼的HER2突变癌细胞。RNA测序确定TORC1信号传导是耐药性的一种可行机制。HER2突变乳腺癌患者患者异种移植物（PDXs）中的原发性和获得性neratinib耐药性也与TORC1过度活跃有关。基因抑制RAPTOR或RHEB消融了P-S6，恢复了对酪氨酸激酶抑制剂的敏感性。TORC1抑制剂依维莫司和neratinib的组合有效抑制了耐neratinib的异种移植物和从耐neratinib的PDX建立的类器官的生长。RNA和全外显子组测序揭示了耐纳替尼耐药模型子集中的RAS介导的TORC1激活。临床上对那拉替尼耐药的HER2突变肿瘤的DNA测序
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