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Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer.
Roper, Nitin; Brown, Anna-Leigh; Wei, Jun S; Pack, Svetlana; Trindade, Christopher; Kim, Chul; Restifo, Olivia; Gao, Shaojian; Sindiri, Sivasish; Mehrabadi, Farid; El Meskini, Rajaa; Ohler, Zoe Weaver; Maity, Tapan K; Venugopalan, Abhilash; Cultraro, Constance M; Akoth, Elizabeth; Padiernos, Emerson; Chen, Haobin; Kesarwala, Aparna; Smart, DeeDee K; Nilubol, Naris; Rajan, Arun; Piotrowska, Zofia; Xi, Liqiang; Raffeld, Mark; Panchenko, Anna R; Sahinalp, Cenk; Hewitt, Stephen; Hoang, Chuong D; Khan, Javed; Guha, Udayan.
Afiliação
  • Roper N; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Brown AL; Present address: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Wei JS; National Center for Biotechnology Information, NIH, NLM, Bethesda, MD 20892, USA.
  • Pack S; Present address: UCL Institute of Neurology and MRC Centre for Neuromuscular Disease, London, UK.
  • Trindade C; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Kim C; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
  • Restifo O; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
  • Gao S; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Sindiri S; Present address: Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC 20007, USA.
  • Mehrabadi F; Present address: Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC 20007, USA.
  • El Meskini R; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Ohler ZW; Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA.
  • Maity TK; Cancer Data Science Laboratory, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Venugopalan A; Center for Advanced Preclinical Research, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Cultraro CM; Center for Advanced Preclinical Research, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Akoth E; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Padiernos E; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Chen H; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Kesarwala A; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Smart DK; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Nilubol N; Thoracic Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Rajan A; Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Piotrowska Z; Present address: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Xi L; Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Raffeld M; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Panchenko AR; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • Sahinalp C; Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Hewitt S; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
  • Hoang CD; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
  • Khan J; National Center for Biotechnology Information, NIH, NLM, Bethesda, MD 20892, USA.
  • Guha U; Present address: Department of Pathology and Molecular Medicine, School of Medicine, Queen's University, Kingston, ON, Canada and Ontario Institute of Cancer Research, Toronto, ON, Canada.
Cell Rep Med ; 1(1)2020 04 21.
Article em En | MEDLINE | ID: mdl-32483558
ABSTRACT
Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as EGFR C797S. MET amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, PD-L1, KRAS amplification, and ESR1-AKAP12, MKRN1-BRAF fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Acrilamidas / Carcinoma Pulmonar de Células não Pequenas / Resistencia a Medicamentos Antineoplásicos / Evolução Clonal / Compostos de Anilina / Neoplasias Pulmonares Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Acrilamidas / Carcinoma Pulmonar de Células não Pequenas / Resistencia a Medicamentos Antineoplásicos / Evolução Clonal / Compostos de Anilina / Neoplasias Pulmonares Idioma: En Ano de publicação: 2020 Tipo de documento: Article