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 - 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 - https://www.scopus.com/pages/publications/85091481593
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 -