TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719X.

Kimihiro Ito,Haruyasu Murakami,Kazutaka Miyadera,Yoshimi Aoyagi,Takashige Okayama,Katsumasa Nonoshita,Akihiro Hashimoto,Hirokazu Ohsawa,Satoru Ito,Kenichi Matsuo,Masanori Kato,Makoto Nishio,Gotaro Tanaka,Yuichiro Ohe

doi:10.1158/1535-7163.mct-18-0645

Abstract

TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. The IC50 for intracellular EGFR phosphorylation was determined by using Jump-In GripTite HEK293 cells transiently transfected with EGFR expression vectors. Mouse xenograft models were used to evaluate the antitumor activity of TAS-121. TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). In addition, TAS-121 showed equivalent inhibitory activity against some uncommon mutations such as G719X and L861Q. Furthermore, TAS-121 demonstrated greater selectivity for mutant EGFRs versus the wild-type EGFR compared with other EGFR-TKIs. Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in patients with NSCLC with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates antitumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.

Highlights

Lung cancer is a leading cause of cancer death worldwide [1]
Ltd. (Supplementary Materials and Methods), erlotinib was purchased from LC Laboratories, osimertinib was purchased from Chemscene, LLC, and afatinib was purchased from Selleck Chemicals
The effect of TAS-121 on EGFR mutants was about 3- to 15fold greater than that on wild-type EGFR. These results suggested that, TAS-121 was effective against EGFR mutations either sensitive or resistant to first-generation EGFR-TKIs (Supplementary Fig. S2A and S2B)

Summary

Introduction

Lung cancer is a leading cause of cancer death worldwide [1]. Discovery of oncogenic kinase mutations, such as activating mutations of the EGFR [2] and rearrangement of anaplastic lymphoma kinase (ALK; refs. 3, 4), and subsequent development of small-molecule kinase inhibitors targeting these kinases has prolonged the progression-free survival (PFS) of patients with NSCLC [5,6,7].The EGFR is the one of the most successful targets for treatment of NSCLC. In patients who received these EGFR-TKIs, the median PFS was about 8 to 12 months, some patients did not show progression for many years. Resistance to these EGFR-TKIs eventually occurs [10, 11]. Many mechanisms of acquired resistance have been reported, such as activation of other kinases 12–14), the epithelial–mesenchymal transition [15], emergence of preexisting small cell clones [16], and point mutation of the EGFR kinase domain gatekeeper (T790M), with this last mechanism being the most frequent cause of resistance [10, 11] Many mechanisms of acquired resistance have been reported, such as activation of other kinases (MET and HER2; refs. 12–14), the epithelial–mesenchymal transition [15], emergence of preexisting small cell clones [16], and point mutation of the EGFR kinase domain gatekeeper (T790M), with this last mechanism being the most frequent cause of resistance [10, 11]

Methods

Results

Conclusion