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Structure-based classification predicts drug response in EGFR-mutant NSCLC.
Robichaux, Jacqulyne P; Le, Xiuning; Vijayan, R S K; Hicks, J Kevin; Heeke, Simon; Elamin, Yasir Y; Lin, Heather Y; Udagawa, Hibiki; Skoulidis, Ferdinandos; Tran, Hai; Varghese, Susan; He, Junqin; Zhang, Fahao; Nilsson, Monique B; Hu, Lemei; Poteete, Alissa; Rinsurongkawong, Waree; Zhang, Xiaoshan; Ren, Chenghui; Liu, Xiaoke; Hong, Lingzhi; Zhang, Jianjun; Diao, Lixia; Madison, Russell; Schrock, Alexa B; Saam, Jennifer; Raymond, Victoria; Fang, Bingliang; Wang, Jing; Ha, Min Jin; Cross, Jason B; Gray, Jhanelle E; Heymach, John V.
Affiliation
  • Robichaux JP; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Le X; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Vijayan RSK; Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX, USA.
  • Hicks JK; Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL, USA.
  • Heeke S; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Elamin YY; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Lin HY; Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.
  • Udagawa H; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Skoulidis F; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Tran H; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Varghese S; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • He J; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Zhang F; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Nilsson MB; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Hu L; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Poteete A; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Rinsurongkawong W; Quantitative Research Computing, MD Anderson Cancer Center, Houston, TX, USA.
  • Zhang X; Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX, USA.
  • Ren C; Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX, USA.
  • Liu X; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Hong L; Department of Thoracic Oncology, West China Medical School, West China Hospital, Sichuan University, Sichuan, China.
  • Zhang J; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Diao L; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Madison R; Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
  • Schrock AB; Foundation Medicine, Cambridge, MA, USA.
  • Saam J; Foundation Medicine, Cambridge, MA, USA.
  • Raymond V; Guardant Health, Redwood City, CA, USA.
  • Fang B; Guardant Health, Redwood City, CA, USA.
  • Wang J; Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX, USA.
  • Ha MJ; Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
  • Cross JB; Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.
  • Gray JE; Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX, USA.
  • Heymach JV; Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA.
Nature ; 597(7878): 732-737, 2021 09.
Article in En | MEDLINE | ID: mdl-34526717
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)1-3. Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations4-6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Lung Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Nature Year: 2021 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Lung Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Nature Year: 2021 Document type: Article Affiliation country: Country of publication: