An inhibitor of mutant EGFR
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, usually due to the acquisition of the resistance mutation. AZD9291 is a oral, potent, and selective third generation irreversible inhibitor of both EGFRm sensitizing and T790M resistance mutants which spares wild-type EGFR.
In vitro: AZD9291 potently inhibits signaling pathways and cellular growth in both EGFRm and EGFRm/T790M mutant cell lines, with lower activity against WT EGFR cell lines. AZD9291 showed an apparent IC50 of 12 nmol/L against L858R and 1 nmol/L against L858R/T790M EGFRm [1].
In vivo: AZD9291 demonstrates good bioavailability, is widely distributed in tissues, and has moderate clearance resulting in a half-life of around 3 hours after oral dosing in the mouse . Once-daily dosing of AZD9291 induced significant dose-dependent regression in both PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models. The tumor shrinkage was observed at doses low to 2.5 mg kg-1 day-1 in both models [1].
Clinical trial: The mesylate salt of AZD9291 is currently in a first-in-human phase I dose-escalation clinical trial (AURA; NCT01802632; AstraZeneca) in patients with advanced EGFRm NSCLC who had disease progression following treatment with any EGFR TKI (including gefitinib or erlotinib). AZD9291 is showing promising responses in this phase I trial even at the first-dose level.
Reference:
[1] Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-61.
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Cell experiment: |
PC-9 cells are seeded into T75 flasks (5×105 cells/flask) in RPMI growth media and incubated at 37°C, 5% CO2. The following day the media is replaced with media supplemented with a concentration of EGFR inhibitor equal to the EC50 concentration predetermined in PC-9 cells. Media changes are carried out every 2-3 days and resistant clones allowed to grow to 80% confluency prior to the cells being trypsinised and reseeded at the original seeding density in media containing twice the concentration of EGFR inhibitor. Dose escalations are continued until a final concentration of 1.5 μM ZD1839, 1.5 μM BIBW 2992, 1.5 μM WZ4002 or 160 nM Osimertinib (AZD-9291) are achieved[1]. |
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Animal experiment: |
Mice[1] The EGFRL858R and EGFRL858R+T790M mice (male and female) are used. Osimertinib (AZD-9291) is suspended in 1% Polysorbate 80 and administered via oral gavage once daily at the doses of 7.5 mg/kg and 5 mg/kg, respectively. Mice are imaged weekly at the Vanderbilt University Institute of Imaging Science. For immunoblot analysis, mice are treated for eight hours with drug as described before dissection and flash freezing of the lungs. Lungs are pulverized in liquid nitrogen before lysis. Rats[2] The male RccHan:WIST rats (10-week-old) are received a single oral dose of Osimertinib (200 mg/kg). Blood glucose levels are measured using an Accuchek Active meter. |
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参考文献: [1]. Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61. |
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