Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma
BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance greatly compromises their therapeutic efficacy. Here, we elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reverses vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Finally, inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro and in vivo in a xenograft model. With the polyamine biosynthesis signature correlated with poor prognosis in BRAF mutant melanoma patients, our findings reveal that the polyamine-hypusination-mitochondrial respiration pathway is an effective therapeutic target that can maximize the therapeutic efficacy of existing BRAF inhibitors. Overall design: The PCR amplicon containing the sgRNA cassette was sequenced with custom primers. The sgRNAs within amplicon was detected with custom codes provided in Github  (https://github.com/tackhoonkim).