Despite dramatic response to first and second-generation EGFR TKIs, resistance emerges over time. The EGFR-T790M mutation accounts for more than half of drug resistance. Third generation (covalent mutation-specific: osimertinib) EGFR TKIs are effective for not only tumors with EGFR-T790M but also other common mutations, EGFR -exon 19 deletions or L858R. A study from Hibiki Udagawa, et al. evaluated TAS6417 as a pan-mutation-selective EGFR TKI with a wide therapeutic window using in vitro and in vivo models.

TAS6417 is a highly effective, orally active and pan-mutation-selective EGFR tyrosine kinase inhibitor with a unique scaffold fitting into the ATP-binding site of the EGFR hinge region, with IC₅₀ values ranging from 1.1-8.0 nM.

In vitro, TAS6417 inhibits EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions. The function resulted in caspase activation. Additionally, TAS6417 covalently modified the cysteine residue at position 797 of recombinant EGFR harboring an in-frame insertion mutation in the exon 20 region. What’s more, TAS6417 inhibits EGFR signal transduction and apoptosis induction in NSCLC cells driven by EGFR exon 20 insertion mutations. It also inhibits cell proliferation and EGFR signaling in NSCLC cell lines harboring EGFR common mutations.

In vivo, TAS6417 (10-200 mg/kg) causes persistent tumor regression in vivo in EGFR exon 20 insertion-driven tumor models. It also inhibits mutant EGFR in tumors but not WT EGFR in skin tissues. However, TAS6417 had no effect on EGFR-independent proliferation in NCI-H23 or NCI-H460 cells. Especially, TAS6417 induceed a significant decrease in pEGFR, leading to reduction of pAKT and pERK at 1 h. The inhibitory effect is still noted at 6 h, and phosphorylation of EGFR, ATK, and ERK recovered by 24 h.

In summary, TAS6417 is a highly effective and pan-mutation-selective EGFR tyrosine kinase inhibitor.

Reference:

Mol Cancer Res. 2019 Nov;17(11):2233-2243.