Clinical and Preclinical Activity of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Harboring BRAF
Alessandro Di Federico1,2, Stefania Angelicola1,3, Mariateresa Frascino4
1Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Purpose:
Patients with tumors harboring BRAF class 3 mutations lack targeted therapies. These mutations are characterized by low/absent BRAF kinase domain activation and are believed to amplify already active RAS signaling, potentially triggered by receptor tyrosine kinases like EGFR.
Materials And Methods:
Two patients with BRAF class 3-mutated metastatic non-small-cell lung cancer (NSCLC) were treated with erlotinib at our Institution after failure of standard therapies. Two cell lines were established from patients with BRAF class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using EGFR-mutated, BRAF class 1 and 2-mutated, and KRAS-mutated NSCLC cell lines as controls.
Results:
Patient 1, a 60-year-old male with BRAFD594N-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAFD594G-mutated NSCLC, achieved partial response to erlotinib after progression on first-line chemoimmunotherapy. High baseline phosphorylated EGFR values and reduced EGFR activation following erlotinib were observed in BRAF class 3-mutated and EGFR-mutated cell lines, but not in BRAF class 1-mutated, BRAF class 2-mutated, or KRAS-mutated lines. Erlotinib inhibited 2-dimensional growth in BRAF class 3-mutated cell lines (IC50 6.33 and 7.11 µM) and in the BRAF class 2-mutated cell line (IC50 5.51 µM), albeit at higher concentrations than in EGFR-mutated lines, whereas it showed no effect on BRAF class 1-mutated (IC50, >25 µM) or KRAS-mutated (IC50, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, BRAF class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with BRAF class 2-mutated and KRAS-mutated lines.
Conclusion:
BRAF class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.
Insights
Patients with BRAF class 3 mutations in non-small cell lung cancer (NSCLC) may benefit from EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study shows promising responses in patients and cell lines treated with erlotinib, suggesting a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumors with BRAF class 3 mutations lack specific targeted therapies.
- These mutations are associated with low BRAF kinase activation and amplified RAS signaling, potentially driven by receptor tyrosine kinases like EGFR.
- Current treatment options for such patients are limited.
Purpose of the Study:
- To investigate the efficacy of erlotinib, an EGFR tyrosine kinase inhibitor (EGFR-TKI), in patients with BRAF class 3-mutated metastatic non-small cell lung cancer (NSCLC).
- To assess the sensitivity of BRAF class 3-mutated NSCLC cell lines to EGFR-TKIs in vitro.
- To explore the potential of BRAF class 3 mutations as a predictive biomarker for EGFR-TKI therapy.
Main Methods:
- Treatment of two patients with BRAF class 3-mutated NSCLC using erlotinib after failure of standard therapies.
- Establishment and in vitro sensitivity assessment of NSCLC cell lines harboring BRAF class 3 mutations to EGFR-TKIs.
- Comparative analysis using NSCLC cell lines with EGFR, BRAF class 1/2, and KRAS mutations as controls.
- Utilized 2D and 3D cell culture assays, including sphere formation, to evaluate drug response.
Main Results:
- Both patients with BRAF class 3 mutations (D594N and D594G) achieved significant responses (complete and partial, respectively) to erlotinib.
- BRAF class 3-mutated and EGFR-mutated cell lines exhibited high baseline phosphorylated EGFR and reduced EGFR activation upon erlotinib treatment.
- Erlotinib demonstrated inhibitory effects on the growth of BRAF class 3-mutated NSCLC cell lines, with IC50 values significantly lower than those for BRAF class 1 or KRAS-mutated lines.
- In vitro and database analyses indicated greater sensitivity of BRAF class 3-mutated NSCLC cell lines to EGFR-TKIs compared to BRAF class 2 and KRAS-mutated lines.
Conclusions:
- BRAF class 3 mutations in NSCLC represent a novel, targetable patient population.
- EGFR-TKIs, such as erlotinib, show potential efficacy in treating NSCLC with BRAF class 3 mutations.
- BRAF class 3 mutations may serve as a predictive biomarker for response to EGFR-TKI therapy in NSCLC.
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