Clinical and Preclinical Activity of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Harboring Class 3 Mutations.

PURPOSE

Patients with tumors harboring 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 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 class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using mutated, class 1 and 2-mutated, and -mutated NSCLC cell lines as controls.

RESULTS

Patient 1, a 60-year-old male with BRAF-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAF-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 class 3-mutated and -mutated cell lines, but not in class 1-mutated, class 2-mutated, or -mutated lines. Erlotinib inhibited 2-dimensional growth in class 3-mutated cell lines (IC 6.33 and 7.11 µM) and in the class 2-mutated cell line (IC 5.51 µM), albeit at higher concentrations than in -mutated lines, whereas it showed no effect on class 1-mutated (IC, >25 µM) or -mutated (IC, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with class 2-mutated and -mutated lines.

CONCLUSION

class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.