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 Rowlinson, Teresa Klinowska, Graham H P Richmond, Mireille Cantarini, Dong-Wan Kim, Malcolm R Ranson, William Pao, 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 Rowlinson, Teresa Klinowska, Graham H P Richmond, Mireille Cantarini, Dong-Wan Kim, Malcolm R Ranson, William Pao
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 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.
Significance: 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.
©2014 American Association for Cancer Research.
Figures
Source: PubMed