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

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), firstand 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 IC 50 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.

HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs

“…In contrast, erlotinib did not induce apoptosis, whereas TAS‐121 as well as osimertinib significantly induced apoptosis in the H1975 cell line (Figure 3(e)). These findings confirm that TAS‐121, a third‐generation EGFR‐TKI, overcomes the EGFR T790M‐driven resistance to erlotinib by a mechanism similar to that of osimertinib 16 …”

“…Here, we report a resistance mechanism of EGFR amplification in a patient with EGFR T790M‐mutated NSCLC who developed acquired resistance to a third‐generation EGFR‐TKI, TAS‐121 16 . We then investigated the role of EGFR amplification in this resistance in vitro.…”

“…However, this limitation has been overcome by the introduction of third‐generation EGFR‐TKIs, such as osimertinib. These compounds covalently bind to the C797 residue within the mutant EGFR kinase domain, irreversibly binding to the ATP‐binding site while sparing wild‐type EGFR 14‐16 . These characteristics of third‐generation EGFR‐TKIs have led to their significant efficacy and decreased toxicity in clinical trials, 17,18 and osimertinib has been approved for the treatment of EGFR ‐positive NSCLC patients 19…”

Evaluation of EGFR-TK Expression with a 99mTc-Labeled Complex Bearing Quinazoline Pharmacophore

“…5,6 Monoclonal antibodies directed against the extracellular ligand binding domain of the receptor and small molecule tyrosine kinase inhibitors (TKIs) directed against the intracellular adenosine triphosphate (ATP) binding site of the tyrosine kinase domain are two classes of drugs approved for clinical use for targeting EGFR. [7][8][9][10] However, the radiolabeled antibodies clear slowly from circulation which causes dose-limiting hematologic toxicity and requires a longer wait time between injection of the radiolabeled antibody and imaging, 11 whereas the TKIs clear quickly from blood, offering a more flexible time window for imaging.…”

Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach

“…Therefore, one of the most critical steps in the covalent drug discovery process is the effective evaluation of their target specificity and assessment of useful derisking strategies 3,4 . The development of modern 'targeted covalent inhibitors' (TCIs) 5,6 has led to significant progress including the successful launch of several preclinical and clinical studies for covalent EGFR inhibitors, such as the FDA approved afatinib (Giltrif) and osimertinib (Tagrisso), which exhibited promising therapeutic effects against resistant cancer models expressing EGFR mutations [7][8][9] . The systematic studies of TCIs have also revealed that the safety of covalent drugs needs to be evaluated on a case-bycase basis and the complexity of the covalent systems often urge innovative approaches [10][11][12] as necessary complements to conventional preclinical and clinical studies.…”