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Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients.
Bray, Steven M; Lee, Jeeyun; Kim, Seung Tae; Hur, Joon Young; Ebert, Philip J; Calley, John N; Wulur, Isabella H; Gopalappa, Thejaswini; Wong, Swee Seong; Qian, Hui-Rong; Ting, Jason C; Liu, Jiangang; Willard, Melinda D; Novosiadly, Ruslan D; Park, Young Suk; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Aggarwal, Amit; Kim, Hee Cheol; Reinhard, Christoph.
Afiliación
  • Bray SM; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Lee J; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Kim ST; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Hur JY; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Ebert PJ; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Calley JN; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Wulur IH; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Gopalappa T; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Wong SS; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Qian HR; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Ting JC; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Liu J; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Willard MD; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Novosiadly RD; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Park YS; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Park JO; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Lim HY; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Kang WK; Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Aggarwal A; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
  • Kim HC; Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hckim@skku.edu.
  • Reinhard C; Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA. REINHARD_CHRISTOPH@lilly.com.
Sci Rep ; 9(1): 15365, 2019 10 25.
Article en En | MEDLINE | ID: mdl-31653970
Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Resistencia a Antineoplásicos / Genómica / Cetuximab Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Colorrectales / Resistencia a Antineoplásicos / Genómica / Cetuximab Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido