TAS3351 is a brain penetrable EGFR-TKI that overcomes T790M and C797S resistant mutations

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Activating mutations in epidermal growth factor receptor (EGFR) drive non-small cell lung cancer (NSCLC) and sensitivity to EGFR-tyrosine kinase inhibitors (TKIs).
• Osimertinib is a standard treatment, but resistance develops, frequently through EGFR C797S mutations.
• Simultaneous T790M and C797S mutations, along with brain metastases, present significant therapeutic challenges due to limited drug penetration.

Purpose of the Study:

• To evaluate TAS3351, a fourth-generation EGFR-TKI, as a potential treatment for NSCLC with acquired resistance mutations.
• To assess TAS3351's efficacy against EGFR T790M and C797S resistance mutations, including dual mutations.
• To determine TAS3351's brain penetrability and efficacy in preclinical models of brain metastasis.

Main Methods:

• Conducted preclinical evaluations of TAS3351, including biochemical, structural, and in vitro/in vivo pharmacological assays.
• Assessed TAS3351's susceptibility to efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP).
• Evaluated TAS3351's brain penetrability and anti-tumor efficacy in mouse models with intracranial allografts.

Main Results:

• TAS3351 demonstrated efficacy in overcoming resistance mediated by EGFR T790M and C797S mutations, while sparing wild-type EGFR.
• TAS3351 is not a substrate for P-gp and BCRP, indicating reduced efflux and potential for better drug exposure.
• Significant brain penetrability was observed, leading to anti-tumor efficacy in preclinical models of brain metastasis.

Conclusions:

• TAS3351 shows promise as a therapeutic candidate for NSCLC patients with tumors resistant to current EGFR-TKIs due to C797S and T790M mutations.
• Its ability to overcome resistance and penetrate the brain makes it a potential treatment option for patients with brain metastases.
• Further clinical investigation of TAS3351 is warranted for NSCLC patients with challenging resistance profiles.