Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M

Kenneth S. Thress, Cloud P. Paweletz, Enriqueta Felip, ByoungChul Cho, Daniel Stetson, Brian Dougherty, Zhongwu Lai, Aleksandra Markovets, Ana Vivancos, Yanan Kuang, Dalia Ercan, Sarah E. Matthews, Mireille Cantarini, J. Carl Barrett, Pasi A. Jänne, Geoffrey R. Oxnard

Research output: Contribution to journalArticle

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Abstract

Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

Original languageEnglish
Pages (from-to)560-562
Number of pages3
JournalNature Medicine
Volume21
Issue number6
DOIs
Publication statusPublished - 2015 Jun 9

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Cells
Mutation
Plasmas
Plasma Cells
Tumors
DNA
Protein-Tyrosine Kinases
AZD9291
Lung Neoplasms
Neoplasms
Cell Line
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Thress, K. S., Paweletz, C. P., Felip, E., Cho, B., Stetson, D., Dougherty, B., ... Oxnard, G. R. (2015). Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nature Medicine, 21(6), 560-562. https://doi.org/10.1038/nm.3854
Thress, Kenneth S. ; Paweletz, Cloud P. ; Felip, Enriqueta ; Cho, ByoungChul ; Stetson, Daniel ; Dougherty, Brian ; Lai, Zhongwu ; Markovets, Aleksandra ; Vivancos, Ana ; Kuang, Yanan ; Ercan, Dalia ; Matthews, Sarah E. ; Cantarini, Mireille ; Barrett, J. Carl ; Jänne, Pasi A. ; Oxnard, Geoffrey R. / Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. In: Nature Medicine. 2015 ; Vol. 21, No. 6. pp. 560-562.
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Thress, KS, Paweletz, CP, Felip, E, Cho, B, Stetson, D, Dougherty, B, Lai, Z, Markovets, A, Vivancos, A, Kuang, Y, Ercan, D, Matthews, SE, Cantarini, M, Barrett, JC, Jänne, PA & Oxnard, GR 2015, 'Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M', Nature Medicine, vol. 21, no. 6, pp. 560-562. https://doi.org/10.1038/nm.3854

Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. / Thress, Kenneth S.; Paweletz, Cloud P.; Felip, Enriqueta; Cho, ByoungChul; Stetson, Daniel; Dougherty, Brian; Lai, Zhongwu; Markovets, Aleksandra; Vivancos, Ana; Kuang, Yanan; Ercan, Dalia; Matthews, Sarah E.; Cantarini, Mireille; Barrett, J. Carl; Jänne, Pasi A.; Oxnard, Geoffrey R.

In: Nature Medicine, Vol. 21, No. 6, 09.06.2015, p. 560-562.

Research output: Contribution to journalArticle

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T1 - Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M

AU - Thress, Kenneth S.

AU - Paweletz, Cloud P.

AU - Felip, Enriqueta

AU - Cho, ByoungChul

AU - Stetson, Daniel

AU - Dougherty, Brian

AU - Lai, Zhongwu

AU - Markovets, Aleksandra

AU - Vivancos, Ana

AU - Kuang, Yanan

AU - Ercan, Dalia

AU - Matthews, Sarah E.

AU - Cantarini, Mireille

AU - Barrett, J. Carl

AU - Jänne, Pasi A.

AU - Oxnard, Geoffrey R.

PY - 2015/6/9

Y1 - 2015/6/9

N2 - Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

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