Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors

Ku Geng Huo, Hirotsugu Notsuda, Zhenhao Fang, Ningdi Feng Liu, Teklab Gebregiworgis, Quan Li, Nhu An Pham, Ming Li, Ni Liu, Frances A. Shepherd, Christopher B. Marshall, Mitsuhiko Ikura, Nadeem Moghal, Ming Sound Tsao

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Introduction: Mutations in BRAF occur in 2% to 4% of patients with lung adenocarcinoma. Combination dabrafenib and trametinib, or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations. Methods: A lung adenocarcinoma patient-derived xenograft model (PHLC12) with wild-type and nonamplified EGFR was tested for response to EGFR tyrosine kinase inhibitors (TKIs). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by small interfering RNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver. Results: Both patient-derived xenograft PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. Small interfering RNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non–EGFR–expressing NR6 cells promoted growth in low serum condition, which was also sensitive to EGFR TKIs. Structural modeling, molecular dynamic simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs. Conclusions: Clinically approved EGFR TKIs can be repurposed to treat patients with non-small cell lung cancer harboring the BRAFG469V mutation.

Original languageEnglish
Pages (from-to)277-288
Number of pages12
JournalJournal of Thoracic Oncology
Volume17
Issue number2
DOIs
Publication statusPublished - 2022 Feb

Keywords

  • Drug repurposing
  • NSCLC
  • Off-target
  • Therapeutics
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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