TY - JOUR
T1 - Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer
AU - Roper, Nitin
AU - Brown, Anna Leigh
AU - Wei, Jun S.
AU - Pack, Svetlana
AU - Trindade, Christopher
AU - Kim, Chul
AU - Restifo, Olivia
AU - Gao, Shaojian
AU - Sindiri, Sivasish
AU - Mehrabadi, Farid
AU - El Meskini, Rajaa
AU - Ohler, Zoe Weaver
AU - Maity, Tapan K.
AU - Venugopalan, Abhilash
AU - Cultraro, Constance M.
AU - Akoth, Elizabeth
AU - Padiernos, Emerson
AU - Chen, Haobin
AU - Kesarwala, Aparna
AU - Smart, Dee Dee K.
AU - Nilubol, Naris
AU - Rajan, Arun
AU - Piotrowska, Zofia
AU - Xi, Liqiang
AU - Raffeld, Mark
AU - Panchenko, Anna R.
AU - Sahinalp, Cenk
AU - Hewitt, Stephen
AU - Hoang, Chuong D.
AU - Khan, Javed
AU - Guha, Udayan
N1 - Funding Information:
We thank the clinical and research nurses as well as palliative care and spiritual care teams for their clinical care of the patients in this study, particularly those who were enrolled in hospice prior to autopsy. We also thank Willie Young and the Pathology residents who assisted with the autopsies. A.-L.B. and A.R.P. thank Drs. Alexander Goncearenco and Alejandro Schaffer for helpful discussions. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (https://hpc.nih.gov/docs/userguide.html). This research was supported by the NIH Intramural Research Program , Center of Cancer Research , and National Cancer Institute and Intramural Research Program of the U.S. National Library of Medicine at the National Institutes of Health . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Funding Information:
We thank the clinical and research nurses as well as palliative care and spiritual care teams for their clinical care of the patients in this study, particularly those who were enrolled in hospice prior to autopsy. We also thank Willie Young and the Pathology residents who assisted with the autopsies. A.-L.B. and A.R.P. thank Drs. Alexander Goncearenco and Alejandro Schaffer for helpful discussions. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (https://hpc.nih.gov/docs/userguide.html). This research was supported by the NIH Intramural Research Program, Center of Cancer Research, and National Cancer Institute and Intramural Research Program of the U.S. National Library of Medicine at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. N.R. C.K. and U.G. designed the study. N.R. A.-L.B. J.S.W. S.P. O.R. C.T. L.X. and J.K. assisted with sample preparation and data analysis. A.-L.B. and N.R. and performed the computational analysis. N.R. performed the biostatistical analyses. S.H. performed the autopsies, and N.R. A.V. and U.G. harvested tissues during autopsies. N.R. C.K. N.N. E.P. E.A. A.R. A.K. D.K.S. C.D.H. and U.G. were involved with clinical care of patients in the clinical trial. N.R. and U.G. wrote the manuscript. All authors reviewed, commented on, and approved the manuscript. C.K. receives research funding to his current institution (Georgetown University) from AstraZeneca, Novartis, and Tesaro and received one-time travel support from CARIS Life Science. C.T. owns stock in Gilead, Celgene, Exelixis, Clovis, and Trevena, and he is an employee of the Food and Drug Administration outside of the submitted work. Z.P. has served as a compensated consultant or received honoraria from AstraZeneca, Spectrum, Ariad/Takeda, Novartis, ImmunoGen, AbbVie, GuardantHealth, Genentech, Eli Lilly, InCyte, and Medtronic and receives institutional research funding from Novartis, Takeda, Spectrum, AstraZeneca, and Tesaro. U.G. has a clinical trial agreement (CTA) with AstraZeneca for the current study and receives research funding from AstraZeneca, Esanex, and Aurigene. U.G. is currently an employee of Bristol Myers Squibb. The other authors have no conflicts of interest to report.
Funding Information:
C.K. receives research funding to his current institution (Georgetown University) from AstraZeneca, Novartis, and Tesaro and received one-time travel support from CARIS Life Science. C.T. owns stock in Gilead, Celgene, Exelixis, Clovis, and Trevena, and he is an employee of the Food and Drug Administration outside of the submitted work. Z.P. has served as a compensated consultant or received honoraria from AstraZeneca, Spectrum, Ariad/Takeda, Novartis, ImmunoGen, AbbVie, GuardantHealth, Genentech, Eli Lilly, InCyte, and Medtronic and receives institutional research funding from Novartis, Takeda, Spectrum, AstraZeneca, and Tesaro. U.G. has a clinical trial agreement (CTA) with AstraZeneca for the current study and receives research funding from AstraZeneca, Esanex, and Aurigene. U.G. is currently an employee of Bristol Myers Squibb. The other authors have no conflicts of interest to report.
Publisher Copyright:
© 2020
PY - 2020/4/21
Y1 - 2020/4/21
N2 - 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.
AB - 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.
KW - EGFR mutant lung cancer
KW - MET amplification
KW - copy number ampplifications
KW - neuroendocrine differentiation
KW - non-small cell lung cancer
KW - osimertinib
UR - http://www.scopus.com/inward/record.url?scp=85091481593&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2020.100007
DO - 10.1016/j.xcrm.2020.100007
M3 - Article
C2 - 32483558
AN - SCOPUS:85091481593
SN - 2666-3791
VL - 1
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 1
M1 - 100007
ER -