NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors

被引:52
作者
Yang, Mengmeng [1 ]
Xu, Xiaoxi [1 ]
Cai, Jie [1 ]
Ning, Jinying [1 ]
Wery, Jean Pierre [1 ]
Li, Qi-Xiang [1 ,2 ]
机构
[1] Crown Biosci Inc, 3375 Scott Blvd,Suite 108, Santa Clara, CA 95054 USA
[2] Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100871, Peoples R China
关键词
PDX; Erbitux; TKI; EGFR-exon-20; insertion; CELL LUNG-CANCER; PATIENT-DERIVED XENOGRAFT; ERLOTINIB; ESTABLISHMENT; RESISTANCE; MUTATIONS; CETUXIMAB; PREDICT; MODELS; PANEL;
D O I
10.1002/ijc.30047
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Anecdote clinical observations hint that non-small cell lung cancer (NSCLC) with exon-20 insertions might respond poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), contrasting to those with classic mutations. Lack of patient-derived experimental models has been a major hurdle for the discovery of new treatment for the diseases. We established two NSCLC-PDXs harboring two different exon-20 insertions, LU0387-adenocarcinoma (ADC) with a nine-base insertion at 2319 (H773-V774insNPH) and LU3075-squamous cell carcinoma (SCC) with a nine-base insertion at 2316 (P772-H773insDNP). Both insertions immediately follow the regulatory C-helix of the kinase domain. Contrary to the generally good responses to EGFR inhibitors observed in PDXs with classic mutations, both exon-20 insertions are largely resistant to cetuximab and TKIs in vivo, suggesting fundamental difference from the classic EGFR mutations, consistent with the poor response rate to TKI seen in anecdotal clinic reports. It is worth noting that although responses are generally poor, they differ between the two exon-20 mutants depending on the type of TKI. In vitro drug sensitivity assays using established primary cell lines from our two PDXs largely confirmed the in vivo data. Our data from patient-derived experimental models confirmed that exon-20 insertions in domain immediately following the C-helix confer poor response to all known EGFR inhibitors, and suggested that these models can be utilized to facilitate the discovery of new therapies targeting NSCLC harboring exon-20 insertions. What's new? Anecdotal clinical observations suggest that, in contrast to classic mutations, non-small cell lung cancers (NSCLCs) with exon-20 insertions respond poorly to EGFR tyrosine kinase inhibitors. The lack of patient-derived experimental models, however, has been a major hurdle for the discovery of new treatments. Here, the authors report establishing for the first time two NSCLC-patient derived xenografts with two different exon-20 insertions, both of them following the C-helix domain. The data confirm that such exon-20 insertions confer poor response to all known EGFR inhibitors. The models may be used to facilitate the discovery of new therapies targeting NSCLCs harboring exon-20 insertions.
引用
收藏
页码:171 / 176
页数:6
相关论文
共 24 条
[1]   Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab [J].
Brand, Toni M. ;
Iida, Mari ;
Wheeler, Deric L. .
CANCER BIOLOGY & THERAPY, 2011, 11 (09) :777-792
[2]   Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma [J].
Bria, Emilio ;
Pilotto, Sara ;
Amato, Eliana ;
Fassan, Matteo ;
Novello, Silvia ;
Peretti, Umberto ;
Vavala, Tiziana ;
Kinspergher, Stefania ;
Righi, Luisella ;
Santo, Antonio ;
Brunelli, Matteo ;
Corbo, Vincenzo ;
Giglioli, Eliana ;
Sperduti, Isabella ;
Milella, Michele ;
Chilosi, Marco ;
Scarpa, Aldo ;
Tortora, Giampaolo .
ONCOTARGET, 2015, 6 (14) :12783-12795
[3]   A set of defined oncogenic mutation alleles seems to better predict the response to cetuximab in CRC patient-derived xenograft than KRAS 12/13 mutations [J].
Chen, Dawei ;
Huang, Xuesong ;
Cai, Jie ;
Guo, Sheng ;
Qian, Wubin ;
Wery, Jean-Pierre ;
Li, Qi-Xiang .
ONCOTARGET, 2015, 6 (38) :40815-40821
[4]   Drug therapy: EGFR antagonists in cancer treatment [J].
Ciardiello, Fortunato ;
Tortora, Giampaolo .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) :1160-1174
[5]   Genome remodelling in a basal-like breast cancer metastasis and xenograft [J].
Ding, Li ;
Ellis, Matthew J. ;
Li, Shunqiang ;
Larson, David E. ;
Chen, Ken ;
Wallis, Johnw. ;
Harris, Christopher C. ;
McLellan, Michael D. ;
Fulton, Robert S. ;
Fulton, Lucinda L. ;
Abbott, Rachel M. ;
Hoog, Jeremy ;
Dooling, David J. ;
Koboldt, Daniel C. ;
Schmidt, Heather ;
Kalicki, Joelle ;
Zhang, Qunyuan ;
Chen, Lei ;
Lin, Ling ;
Wendl, Michael C. ;
McMichael, Joshua F. ;
Magrini, Vincent J. ;
Cook, Lisa ;
McGrath, Sean D. ;
Vickery, Tammi L. ;
Appelbaum, Elizabeth ;
DeSchryver, Katherine ;
Davies, Sherri ;
Guintoli, Therese ;
Lin, Li ;
Crowder, Robert ;
Tao, Yu ;
Snider, Jacqueline E. ;
Smith, Scott M. ;
Dukes, Adam F. ;
Sanderson, Gabriel E. ;
Pohl, Craig S. ;
Delehaunty, Kim D. ;
Fronick, Catrina C. ;
Pape, Kimberley A. ;
Reed, Jerry S. ;
Robinson, Jody S. ;
Hodges, Jennifer S. ;
Schierding, William ;
Dees, Nathan D. ;
Shen, Dong ;
Locke, Devin P. ;
Wiechert, Madeline E. ;
Eldred, James M. ;
Peck, Josh B. .
NATURE, 2010, 464 (7291) :999-1005
[6]   Establishment of Patient-Derived Non-Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers [J].
Fichtner, Iduna ;
Rolff, Jana ;
Soong, Richie ;
Hoffmann, Jens ;
Hammer, Stefanie ;
Sommer, Anette ;
Becker, Michael ;
Merk, Johannes .
CLINICAL CANCER RESEARCH, 2008, 14 (20) :6456-6468
[7]   Antitumor activity of erlotinib in combination with gemcitabine in in vitro and in vivo models of KRAS-mutated pancreatic cancers [J].
Furugaki, Koh ;
Iwai, Toshiki ;
Kondoh, Kumiko ;
Moriya, Yoichiro ;
Mori, Kazushige .
ONCOLOGY LETTERS, 2010, 1 (02) :231-235
[8]   High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response [J].
Gao, Hui ;
Korn, Joshua M. ;
Ferretti, Stephane ;
Monahan, John E. ;
Wang, Youzhen ;
Singh, Mallika ;
Zhang, Chao ;
Schnell, Christian ;
Yang, Guizhi ;
Zhang, Yun ;
Balbin, O. Alejandro ;
Barbe, Stephanie ;
Cai, Hongbo ;
Casey, Fergal ;
Chatterjee, Susmita ;
Chiang, Derek Y. ;
Chuai, Shannon ;
Cogan, Shawn M. ;
Collins, Scott D. ;
Dammassa, Ernesta ;
Ebel, Nicolas ;
Embry, Millicent ;
Green, John ;
Kauffmann, Audrey ;
Kowa, Colleen ;
Leary, Rebecca J. ;
Lehar, Joseph ;
Liang, Ying ;
Loo, Alice ;
Lorenzana, Edward ;
McDonald, E. Robert, III ;
McLaughlin, Margaret E. ;
Merkin, Jason ;
Meyer, Ronald ;
Naylor, Tara L. ;
Patawaran, Montesa ;
Reddy, Anupama ;
Roeelli, Claudia ;
Ruddy, David A. ;
Salangsang, Fernando ;
Santacroce, Francesca ;
Singh, Angad P. ;
Tang, Yan ;
Tinetto, Walter ;
Tobler, Sonja ;
Velazquez, Roberto ;
Venkatesan, Kavitha ;
Von Arx, Fabian ;
Wang, Hui Qin ;
Wang, Zongyao .
NATURE MEDICINE, 2015, 21 (11) :1318-1325
[9]   Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas [J].
Gao, Sizhi Paul ;
Mark, Kevin G. ;
Leslie, Kenneth ;
Pao, William ;
Motoi, Noriko ;
Gerald, William L. ;
Travis, William D. ;
Bornmann, William ;
Veach, Darren ;
Clarkson, Bayard ;
Bromberg, Jacqueline F. .
JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (12) :3846-3856
[10]   Promoter Methylation in Head and Neck Squamous Cell Carcinoma Cell Lines Is Significantly Different than Methylation in Primary Tumors and Xenografts [J].
Hennessey, Patrick T. ;
Ochs, Michael F. ;
Mydlarz, Wojciech W. ;
Hsueh, Wayne ;
Cope, Leslie ;
Yu, Wayne ;
Califano, Joseph A. .
PLOS ONE, 2011, 6 (05)