Lung Cancer Driven by BRAF^G469V Mutation Is Targetable by EGFR Kinase Inhibitors.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• BRAF mutations occur in 2-4% of lung adenocarcinoma cases.
• Current targeted therapies, like dabrafenib, trametinib, and vemurafenib, are approved only for the BRAF V600E mutation.
• No targeted therapy is available for patients with non-V600 BRAF mutations.

Purpose of the Study:

• To investigate the efficacy of EGFR tyrosine kinase inhibitors (TKIs) against non-V600 BRAF mutations in lung adenocarcinoma.
• To identify the specific oncogenic driver in a patient-derived xenograft model (PHLC12) and its derived cell line (X12CL).
• To explore the mechanism of off-target inhibition of BRAF mutations by EGFR TKIs.

Main Methods:

• Utilized a lung adenocarcinoma patient-derived xenograft model (PHLC12) and its cell line (X12CL).
• Performed small interfering RNA (siRNA) knockdown to identify the oncogenic driver.
• Conducted kinase assays, structural modeling, molecular dynamics simulations, and in vitro binding assays to assess drug sensitivity and mechanism of action.

Main Results:

• The BRAF G469V mutation was identified as the sole oncogenic driver in the PHLC12 model.
• Both the xenograft model and cell line showed sensitivity to multiple EGFR TKIs.
• EGFR TKIs, including gefitinib and osimertinib, directly inhibited BRAF G469V kinase activity.
• Expression of BRAF G469V in non-EGFR-expressing cells conferred sensitivity to EGFR TKIs.

Conclusions:

• Clinically approved EGFR TKIs can be repurposed for treating non-small cell lung cancer with the BRAF G469V mutation.
• This finding expands therapeutic options for lung adenocarcinoma patients with specific non-V600 BRAF alterations.