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; Dee Dee 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

doi:10.1016/j.xcrm.2020.100007

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, Dee Dee K. SmartNaris Nilubol, Arun Rajan, Zofia Piotrowska, Liqiang Xi, Mark Raffeld, Anna R. Panchenko, Cenk Sahinalp, Stephen Hewitt, Chuong D. Hoang, Javed Khan, Udayan Guha

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115 Scopus citations

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.

Original language	English
Article number	100007
Journal	Cell Reports Medicine
Volume	1
Issue number	1
DOIs	https://doi.org/10.1016/j.xcrm.2020.100007
State	Published - Apr 21 2020

Keywords

EGFR mutant lung cancer
MET amplification
copy number ampplifications
neuroendocrine differentiation
non-small cell lung cancer
osimertinib

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10.1016/j.xcrm.2020.100007

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Roper, N., Brown, A. L., Wei, J. S., Pack, S., Trindade, C., Kim, C., Restifo, O., Gao, S., Sindiri, S., Mehrabadi, F., El Meskini, R., Ohler, Z. W., Maity, T. K., Venugopalan, A., Cultraro, C. M., Akoth, E., Padiernos, E., Chen, H., Kesarwala, A., ... Guha, U. (2020). Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer. Cell Reports Medicine, 1(1), Article 100007. https://doi.org/10.1016/j.xcrm.2020.100007

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title = "Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer",

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.",

keywords = "EGFR mutant lung cancer, MET amplification, copy number ampplifications, neuroendocrine differentiation, non-small cell lung cancer, osimertinib",

author = "Nitin Roper and Brown, {Anna Leigh} and Wei, {Jun S.} and Svetlana Pack and Christopher Trindade and Chul Kim and Olivia Restifo and Shaojian Gao and Sivasish Sindiri and Farid Mehrabadi and {El Meskini}, Rajaa and Ohler, {Zoe Weaver} and Maity, {Tapan K.} and Abhilash Venugopalan and Cultraro, {Constance M.} and Elizabeth Akoth and Emerson Padiernos and Haobin Chen and Aparna Kesarwala and Smart, {Dee Dee K.} and Naris Nilubol and Arun Rajan and Zofia Piotrowska and Liqiang Xi and Mark Raffeld and Panchenko, {Anna R.} and Cenk Sahinalp and Stephen Hewitt and Hoang, {Chuong D.} and Javed Khan and Udayan Guha",

note = "Publisher Copyright: {\textcopyright} 2020",

year = "2020",

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doi = "10.1016/j.xcrm.2020.100007",

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Roper, N, Brown, AL, Wei, JS, Pack, S, Trindade, C, Kim, C, Restifo, O, Gao, S, Sindiri, S, Mehrabadi, F, El Meskini, R, Ohler, ZW, Maity, TK, Venugopalan, A, Cultraro, CM, Akoth, E, Padiernos, E, Chen, H, Kesarwala, A, Smart, DDK, Nilubol, N, Rajan, A, Piotrowska, Z, Xi, L, Raffeld, M, Panchenko, AR, Sahinalp, C, Hewitt, S, Hoang, CD, Khan, J & Guha, U 2020, 'Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer', Cell Reports Medicine, vol. 1, no. 1, 100007. https://doi.org/10.1016/j.xcrm.2020.100007

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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

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

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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 -

Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer

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