Abstract LB_B10: Non-V600 BRAF mutants and their precise targeting

Abstract

Abstract Hyperactive RAS/RAF/MEK/ERK signalling is responsible for a large portion of cancers and targeting this signalling pathway has achieved a promising outcome in clinic cancer treatment. However, significant challenges such as drug resistance are still existing. To resolve these problems, we need a deeper understanding of the regulatory mechanism and hence develop better targeting approaches against this signalling pathway. In this study, we investigated the molecular mechanism that controls that activity of BRAF, a key component of this signalling pathway, and found that BRAF cycled between inactive monomeric status and active dimeric status, which is coordinatively regulated by Cdc37/Hsp90 chaperone and 14-3-3 scaffold. Further, we found that most non-V600 mutations of BRAF in cancer genomes undermined this regulatory mechanism through disturbing the association of BRAF with Cdc37/Hsp90 chaperone or 14-3-3 scaffold and hence trapped BRAF in active dimeric status. Given the high dimer affinity of these non-V600 BRAF mutants, we next examined whether their activity could be inhibited effectively RAF dimer breaker PLX8394 in vitro and in vivo. Indeed, we found that in contrast to clinic RAF inhibitor Vemurafenib (PLX4720), PLX8394 strongly inhibited the activity of non-V600 BRAF mutants and induced a rapid regression of fibroblastomas driven by non-V600 BRAF mutants. Together, our data clearly illustrates how oncogenic non-V600 mutations break down the regulation of BRAF by Cdc37/Hsp90 chaperone and 14-3-3 scaffold, and how these BRAF mutations could be precisely targeted by RAF dimer breaker, which has important implications for anti-BRAF cancer therapy. Citation Format: Jiancheng Hu. Non-V600 BRAF mutants and their precise targeting [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B10.