Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations

Activating mutations in the epidermal growth factor receptor (EGFR), particularly exon 19 deletions and L858R mutation, are frequently observed in non-small cell lung cancer (NSCLC) and confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, resistance mutations such as T790M and C797S lead to refractory to EGFR-TKIs and ultimately to progression of the disease. In addition, brain metastasis often causes disease progression due to reduced drug penetration into the brain. Here, we demonstrate that TAS3351, a novel fourth-generation EGFR-TKI, overcomes resistance due to T790M and C797S mutations while sparing wild-type EGFR activity. Furthermore, TAS3351 is not a substrate of the efflux transporters and exhibits significant brain penetrability, resulting in high efficacy in mouse models with intracranial allografts. These findings indicate that TAS3351 is a promising therapeutic candidate for patients with NSCLC who have relapsed and are refractory to treatment due to C797S and T790M resistance mutations, including those with brain metastases.