Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

Jacob J. Chabon; Andrew D. Simmons; Alexander F. Lovejoy; Mohammad S. Esfahani; Aaron M. Newman; Henry J. Haringsma; David M. Kurtz; Henning Stehr; Florian Scherer; Chris A. Karlovich; Thomas C. Harding; Kathleen A. Durkin; Gregory A. Otterson; W. Thomas Purcell; D. Ross Camidge; Jonathan W. Goldman; Lecia V. Sequist; Zofia Piotrowska; Heather A. Wakelee; Joel W. Neal; Ash A. Alizadeh; Maximilian Diehn

doi:10.1038/ncomms11815

Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

Jacob J. Chabon, Andrew D. Simmons, Alexander F. Lovejoy, Mohammad S. Esfahani, Aaron M. Newman, Henry J. Haringsma, David M. Kurtz, Henning Stehr, Florian Scherer, Chris A. Karlovich, Thomas C. Harding, Kathleen A. Durkin, Gregory A. Otterson, W. Thomas Purcell, D. Ross Camidge, Jonathan W. Goldman, Lecia V. Sequist, Zofia Piotrowska, Heather A. Wakelee, Joel W. NealAsh A. Alizadeh, Maximilian Diehn

School of Medicine

Research output: Contribution to journal › Article › peer-review

357 Scopus citations

Abstract

Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in â '1/433% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

Original language	English (US)
Article number	11815
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11815
State	Published - Jun 10 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., ... Diehn, M. (2016). Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nature communications, 7, [11815]. https://doi.org/10.1038/ncomms11815

Chabon, JJ, Simmons, AD, Lovejoy, AF, Esfahani, MS, Newman, AM, Haringsma, HJ, Kurtz, DM, Stehr, H, Scherer, F, Karlovich, CA, Harding, TC, Durkin, KA, Otterson, GA, Purcell, WT, Camidge, DR, Goldman, JW, Sequist, LV, Piotrowska, Z, Wakelee, HA, Neal, JW, Alizadeh, AA & Diehn, M 2016, 'Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients', Nature communications, vol. 7, 11815. https://doi.org/10.1038/ncomms11815

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title = "Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients",

abstract = "Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in {\^a} '1/433% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.",

author = "Chabon, {Jacob J.} and Simmons, {Andrew D.} and Lovejoy, {Alexander F.} and Esfahani, {Mohammad S.} and Newman, {Aaron M.} and Haringsma, {Henry J.} and Kurtz, {David M.} and Henning Stehr and Florian Scherer and Karlovich, {Chris A.} and Harding, {Thomas C.} and Durkin, {Kathleen A.} and Otterson, {Gregory A.} and Purcell, {W. Thomas} and Camidge, {D. Ross} and Goldman, {Jonathan W.} and Sequist, {Lecia V.} and Zofia Piotrowska and Wakelee, {Heather A.} and Neal, {Joel W.} and Alizadeh, {Ash A.} and Maximilian Diehn",

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AU - Chabon, Jacob J.

AU - Simmons, Andrew D.

AU - Lovejoy, Alexander F.

AU - Esfahani, Mohammad S.

AU - Newman, Aaron M.

AU - Haringsma, Henry J.

AU - Kurtz, David M.

AU - Stehr, Henning

AU - Scherer, Florian

AU - Karlovich, Chris A.

AU - Harding, Thomas C.

AU - Durkin, Kathleen A.

AU - Otterson, Gregory A.

AU - Purcell, W. Thomas

AU - Camidge, D. Ross

AU - Goldman, Jonathan W.

AU - Sequist, Lecia V.

AU - Piotrowska, Zofia

AU - Wakelee, Heather A.

AU - Neal, Joel W.

AU - Alizadeh, Ash A.

AU - Diehn, Maximilian

PY - 2016/6/10

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N2 - Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in â '1/433% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

AB - Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in â '1/433% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

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Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

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