Osimertinib (AZD9291) is an Orally Active EGFR Inhibitor for Lung Cancer Research

EGFR-mutated (EGFRm⁺) non-small cell lung cancer (NSCLC) is a major clinical problem. Tyrosine kinase inhibitors (TKIs) have precision therapeutic implications for advanced NSCLC. However, common EGFR mutations, such as EGFR^L858R, lead to limitations in the use of EGFR TKIs. The second mutation, EGFR^T790M, leading to the mechanism of EGFR TKI resistance. But most first-generation TKIs inhibit wild-type EGFR leading to side effects and toxicity. Therefore, there is an urgent need to discover a potent EGFR TKI that effectively targets T790M tumors while retaining wild-type EGFR activity. Here we introduce an EGFR TKI, Osimertinib (AZD9291), targeting EGFRm⁺ sensitized and T790M resistant mutants. And it does not affect wild-type EGFR.

Osimertinib is a covalently bound, irreversible EGFR inhibitor with orally active biological activity.

In vitro studies, Osimertinib inhibits signaling pathways and cell growth in EGFRm⁺ and EGFRm⁺/T790M⁺ mutant cell lines. It inhibits EGFR phosphorylation, and inhibits cell proliferation on L858R (IC₅₀=12 nM) and L858R/T790M (IC₅₀=1 nM). Osimertinib (0-10 μM; 72 hours) inhibits the proliferation of Ba/F3 cells harboring the T790M mutation, exon 19del+T790M, or L858R+T790M. The mean IC₅₀ is 8 nM against the sensitizing mutant (PC-9 cells), and the mean IC₅₀ is 11 and 40 nM against the T790M mutant H1975 and PC-9VanR cells, respectively. And it inhibits Ba/F3 cells harboring EGFR exon 20 insertion mutations.

Osimertinib significantly inhibits mouse EGFR in vivo transgenic tumor models and mutant EGFR in vivo xenograft models. It (0.1-25 mg/kg/day; orally administration for 14 days) effectively targets T790M tumors in PC-9 (ex19del) and H1975 (L858R/T790M) tumor xenograft models. Significantly results in tumor growth inhibition at a dose of 5 mg/kg/day. It also strongly inhibits mutant EGFR phosphorylation and downstream signaling pathways, but does not affect wild-type EGFR activity.

In summary, Osimertinib is an orally active and potent EGFR mutant TK inhibitor. It is capable of targeting common activating/sensitizing EGFR mutants without toxicity to wild-type EGFR. Osimertinib, as the third-generation EGFR TKI, is of great help in solving the sensitivity or drug resistance of NSCLC.

References:

[1]. Cross DA, et al. Cancer Discov. 2014 Sep;4(9):1046-61.  

[2]. Hirano T, et al. Mol Cancer Ther. 2018 Apr;17(4):740-750.