Combined inhibition of BRAF/MEK and mTOR/Akt/PI3K pathways in BRAF-V600 mutated lung adenocarcinoma

Current guidelines recommend the treatment of BRAF-V600-mutated lung adenocarcinoma with the combination of 2nd generation BRAF and MEK inhibitors, namely dabrafenib plus tramenitinib. However, the majority of patients show no response or develop resistance during treatment by various resistance mechanisms including activation of additional signaling networks. Accordingly, we aim to characterize the response of a novel, malignant pleural effusion derived cell line to currently approved inhibitors using cell viability, cell cycle and immunoblot assays.

First, we demonstrated in single agent treatments that dabrafenib and encorafenib showed an increased growth inhibition when compared to vemurafenib. The approved combination treatments (dabrafenib plus tramenitinib and encorafenib plus binimetinib) showed a synergistic growth inhibition, however, the induction of apoptosis was limited even in the combinations. Importantly, we found that activation of Akt is increased upon BRAF/MEK inhibition. For this very reason, we combined trametinib with the approved Akt and PI3K inhibitors capivasertib and alpelisib, respectively. The concomitant inhibition of the BRAF/MEK and MTOR/AKT/PI3K pathways resulted in a synergistic growth inhibition, increased apoptosis induction, and reduced ratio of cells in S phase.

Our results show that dual inhibition of MAPK- and mTOR/AKT/PI3K-pathway might be a novel therapeutic option for BRAF-mutated lung adenocarcinoma.

Publication History

Article published online:
09 March 2023