Cell Reports Medicine (Apr 2020)
Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer
- Nitin Roper,
- Anna-Leigh Brown,
- Jun S. Wei,
- Svetlana Pack,
- Christopher Trindade,
- Chul Kim,
- Olivia Restifo,
- Shaojian Gao,
- Sivasish Sindiri,
- Farid Mehrabadi,
- Rajaa El Meskini,
- Zoe Weaver Ohler,
- Tapan K. Maity,
- Abhilash Venugopalan,
- Constance M. Cultraro,
- Elizabeth Akoth,
- Emerson Padiernos,
- Haobin Chen,
- Aparna Kesarwala,
- DeeDee K. Smart,
- Naris Nilubol,
- Arun Rajan,
- Zofia Piotrowska,
- Liqiang Xi,
- Mark Raffeld,
- Anna R. Panchenko,
- Cenk Sahinalp,
- Stephen Hewitt,
- Chuong D. Hoang,
- Javed Khan,
- Udayan Guha
Affiliations
- Nitin Roper
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA; Corresponding author
- Anna-Leigh Brown
- National Center for Biotechnology Information, NIH, NLM, Bethesda, MD 20892, USA
- Jun S. Wei
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Svetlana Pack
- Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Christopher Trindade
- Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Chul Kim
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Olivia Restifo
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA; Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Shaojian Gao
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Sivasish Sindiri
- Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Farid Mehrabadi
- Cancer Data Science Laboratory, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Rajaa El Meskini
- Center for Advanced Preclinical Research, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Zoe Weaver Ohler
- Center for Advanced Preclinical Research, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Tapan K. Maity
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Abhilash Venugopalan
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Constance M. Cultraro
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Elizabeth Akoth
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Emerson Padiernos
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Haobin Chen
- Thoracic Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Aparna Kesarwala
- Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- DeeDee K. Smart
- Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Naris Nilubol
- Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Arun Rajan
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Zofia Piotrowska
- Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Liqiang Xi
- Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Mark Raffeld
- Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Anna R. Panchenko
- National Center for Biotechnology Information, NIH, NLM, Bethesda, MD 20892, USA
- Cenk Sahinalp
- Cancer Data Science Laboratory, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Stephen Hewitt
- Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
- Chuong D. Hoang
- Thoracic Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Javed Khan
- Genetics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA; Corresponding author
- Udayan Guha
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA; Corresponding author
- Journal volume & issue
-
Vol. 1,
no. 1
p. 100007
Abstract
Summary: 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.
