AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

Darren A E Cross, Susan E. Ashton, Serban Ghiorghiu, Cath Eberlein, Caroline A. Nebhan, Paula J. Spitzler, Jonathon P. Orme, M. Raymond V Finlay, Richard A. Ward, Martine J. Mellor, Gareth Hughes, Amar Rahi, Vivien N. Jacobs, Monica Red Brewer, Eiki Ichihara, Jing Sun, Hailing Jin, Peter Ballard, Katherine Al-Kadhimi, Rachel RowlinsonTeresa Klinowska, Graham H P Richmond, Mireille Cantarini, Dong Wan Kim, Malcolm R. Ranson, William Pao

Research output: Contribution to journalArticle

801 Citations (Scopus)

Abstract

First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective thirdgeneration irreversible inhibitor of both EGFRm+sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+and EGFRm/T790M+mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm+T790M+NSCLC is described as proof of principle. We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M+ mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.

Original languageEnglish
Pages (from-to)1046-1061
Number of pages16
JournalCancer Discovery
Volume4
Issue number9
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Protein-Tyrosine Kinases
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Heterografts
Disease Progression
Neoplasms
Cell Line
Mutation
Growth
Pharmaceutical Preparations
AZD9291
Therapeutics
In Vitro Techniques
pyrimidine

ASJC Scopus subject areas

  • Oncology

Cite this

Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., ... Pao, W. (2014). AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discovery, 4(9), 1046-1061. https://doi.org/10.1158/2159-8290.CD-14-0337

AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. / Cross, Darren A E; Ashton, Susan E.; Ghiorghiu, Serban; Eberlein, Cath; Nebhan, Caroline A.; Spitzler, Paula J.; Orme, Jonathon P.; Finlay, M. Raymond V; Ward, Richard A.; Mellor, Martine J.; Hughes, Gareth; Rahi, Amar; Jacobs, Vivien N.; Brewer, Monica Red; Ichihara, Eiki; Sun, Jing; Jin, Hailing; Ballard, Peter; Al-Kadhimi, Katherine; Rowlinson, Rachel; Klinowska, Teresa; Richmond, Graham H P; Cantarini, Mireille; Kim, Dong Wan; Ranson, Malcolm R.; Pao, William.

In: Cancer Discovery, Vol. 4, No. 9, 2014, p. 1046-1061.

Research output: Contribution to journalArticle

Cross, DAE, Ashton, SE, Ghiorghiu, S, Eberlein, C, Nebhan, CA, Spitzler, PJ, Orme, JP, Finlay, MRV, Ward, RA, Mellor, MJ, Hughes, G, Rahi, A, Jacobs, VN, Brewer, MR, Ichihara, E, Sun, J, Jin, H, Ballard, P, Al-Kadhimi, K, Rowlinson, R, Klinowska, T, Richmond, GHP, Cantarini, M, Kim, DW, Ranson, MR & Pao, W 2014, 'AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer', Cancer Discovery, vol. 4, no. 9, pp. 1046-1061. https://doi.org/10.1158/2159-8290.CD-14-0337
Cross, Darren A E ; Ashton, Susan E. ; Ghiorghiu, Serban ; Eberlein, Cath ; Nebhan, Caroline A. ; Spitzler, Paula J. ; Orme, Jonathon P. ; Finlay, M. Raymond V ; Ward, Richard A. ; Mellor, Martine J. ; Hughes, Gareth ; Rahi, Amar ; Jacobs, Vivien N. ; Brewer, Monica Red ; Ichihara, Eiki ; Sun, Jing ; Jin, Hailing ; Ballard, Peter ; Al-Kadhimi, Katherine ; Rowlinson, Rachel ; Klinowska, Teresa ; Richmond, Graham H P ; Cantarini, Mireille ; Kim, Dong Wan ; Ranson, Malcolm R. ; Pao, William. / AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. In: Cancer Discovery. 2014 ; Vol. 4, No. 9. pp. 1046-1061.
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AU - Ichihara, Eiki

AU - Sun, Jing

AU - Jin, Hailing

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