Details

Autor(en) / Beteiligte

• 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
• Red Brewer, Monica
• 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

Titel

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

Ist Teil von

• Cancer discovery, 2014-09, Vol.4 (9), p.1046-1061

Ort / Verlag

United States

Erscheinungsjahr

2014

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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 third-generation 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.