title: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oncology Innovative Medicines and Darren.Cross@astrazeneca.com william.pao@vanderbilt.edu.
authors.forename: Darren A E
authors.initials: DA
authors.lastname: Cross
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ashton
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Serban
authors.initials: S
authors.lastname: Ghiorghiu
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Cath
authors.initials: C
authors.lastname: Eberlein
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Nebhan
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Spitzler
authors.affiliation: Discovery Sciences, AstraZeneca, Macclesfield Cheshire;
authors.forename: Jonathon P
authors.initials: JP
authors.lastname: Orme
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: M Raymond V
authors.initials: MR
authors.lastname: Finlay
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Mellor
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Gareth
authors.initials: G
authors.lastname: Hughes
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Amar
authors.initials: A
authors.lastname: Rahi
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Vivien N
authors.initials: VN
authors.lastname: Jacobs
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Monica
authors.initials: M
authors.lastname: Red Brewer
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
authors.forename: Hailing
authors.initials: H
authors.lastname: Jin
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Al-Kadhimi
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rowlinson
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Graham H P
authors.initials: GH
authors.lastname: Richmond
authors.affiliation: Oncology Innovative Medicines and.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cantarini
authors.affiliation: Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: University of Manchester, Christie Hospital, Manchester, United Kingdom;
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Ranson
authors.affiliation: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and Darren.Cross@astrazeneca.com william.pao@vanderbilt.edu.
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines