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TAS3351 is a brain penetrable EGFR-TKI that overcomes T790M and C797S resistant mutations
Hidefumi Kasuga1, Yuki Kataoka2, Fuyuki Yamamoto2
1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan. h-kasuga@taiho.co.jp.
Background:
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). Among these EGFR-TKIs, osimertinib is currently the standard of care for patients with NSCLC harboring the activating mutations. However, resistant mutations often arise, leading to resistance to osimertinib. The resistant mutation that most frequently occurs in EGFR during osimertinib treatment is the C797S mutation. Another major resistant mutation arising in EGFR during treatment with other EGFR-TKIs, such as gefitinib and afatinib, is the T790M mutation. Currently, no approved EGFR-TKIs are effective in patients who simultaneously develop the T790M and C797S mutations. Additionally, brain metastasis often causes disease progression due to reduced drug penetration into the brain.
Methods:
We conducted preclinical evaluations of TAS3351, a fourth-generation EGFR-TKI, including biochemical, structural, and in vitro/in vivo pharmacological assays. We also evaluated the efflux transporter susceptibility and brain penetrability of TAS3351 in male mice.
Results:
Here, we demonstrate that TAS3351 overcomes resistance due to T790M and C797S mutations while sparing wild-type EGFR activity. Furthermore, TAS3351 is not a substrate of P-glycoprotein (P-gp) and the breast cancer-resistant protein (BCRP) and exhibits significant brain penetrability, resulting in anti-tumor efficacy in mice with intracranial allografts.
Conclusions:
These findings indicate that TAS3351 is a promising therapeutic candidate for patients with NSCLC whose tumors have relapsed or are refractory to treatment due to the C797S and T790M mutations, and the brain metastases.
Insights
A new drug, TAS3351, effectively treats non-small cell lung cancer (NSCLC) resistant to other therapies. It targets specific EGFR mutations and penetrates the brain, offering hope for advanced disease.
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.
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