SH003 enhances the anti-cancer effects of Dabrafenib on lung cancer harboring BRAF G469A mutation by inhibiting the MAPK signaling pathway

Abstract BRAF mutations are relatively uncommon in lung cancer. However, the majority of therapies targeting BRAF mutations have been developed exclusively for lung cancer patients with V600E mutations, limiting their effectiveness in treating tumors with the non-V600E BRAF mutations. As a result, there is a need to explore effective therapeutic strategies for lung cancer patients carrying non-V600 BRAF mutations. In this study, we demonstrated that the lung cancer cells harboring the non-V600E G469A mutation were responsive to the combination of SH003 and dabrafenib. By utilizing patient-derived xenograft (PDX) models, we identified that this combined treatment induces apoptosis and exhibited antitumor effects through the reduction of ERK signals. The synergistic effect of the combination treatment on BRAF G469A lung cancer cells was consistent with its effects in PDX models, suggesting that the molecular mechanism of apoptosis involves a decrease in the MEK/ERK signaling pathway. These findings propose the potential development of the SH003 and dabrafenib combination treatment as an effective strategy for addressing lung cancer patients with BRAF G469A mutation.