The effect of Gefitinib on B-RAF mutant non-small-cell lung cancer and transfectants Free

2023

Previous studies indicated that EGFR-TKIs revealed responsiveness in approximately 80% of EGFR mutant tumors, however, no drug sensitizing EGFR mutation was found in the rest 20%, suggesting that other factors such as increased copy number of EGFR may cause tumor response to drug. We previously reported one patient with squamous cell carcinoma (SCC) of the lung that showed the long-term effect to gefitinib with complete response. We examined the epidermal growth factor receptor (EGFR), K-RAS, HER2, and B-RAF mutations in this patient to find a B-RAF exon11 mutation, resulting in a substitution of valine by phenylalanine at codon 470 (V470F) as a novel type of B-RAF mutation in human cancers. B-RAFis a nonreceptor serine/threonine kinase of which kinase domain has a structure similar as other protein kinases, including EGFR members. Of interest, the B-RAF V470F mutation is corresponded to a similar position as the EGFR G719X mutation located on the phosphate binding (P)-loop of EGFR that clamps ATP into catalytic cleft. This observation suggests that gefitinib may have the anti-cancer effect on B-RAF mutant tumors. Indeed, previous reports demonstrated that H1666 cells harboring B-RAF G465V mutation showed sensitivity to gefitinib, inhibiting phosphorylation of Erk1/2. We examined the effect of gefitinib on transient transfectants of B-RAF mutant (G468E, V470F, and V599E), but no drastic inhibition of Erk1/2 phosphorylation that was one of downstream molecules of B-RAF was induced by gefitinib. Whereas the long-term effect of gefitinib in our patient may be due to other mechanisms including the increased EGFR copy number, the fact that the mutant B-RAF caused the activation of the MEK-ERK cascade for proliferation, regardless of the blockage of EGFR activation by gefitinib, may explain the possibility that the B-RAF mutant protein could play a critical role in tumor response to gefitinib. In summary, a novel B-RAF V470F mutation in lung SCC that showed response to gefitinib was found. However, our investigation in vitro did not support our finding in this particular patient. Further investigation is necessary to elucidate the mechanism to determine tumor sensitivity to EGFR tyrosine kinase inhibitors.