Propranolol overcomes vemurafenib resistance in melanoma by upregulating CDK11 and inducing cell cycle arrest
Acquired resistance to the BRAF inhibitor vemurafenib remains a major obstacle in melanoma therapy. Drug repurposing offers a promising strategy to overcome such resistance. Here, we investigated the ß-blocker propranolol as a sensitizer to vemurafenib in resistant melanoma. Using vemurafenib-resistant cell lines (A375-VR and patient-derived P-8-VR), we found that propranolol restored vemurafenib sensitivity both in vitro and in vivo. RNA sequencing revealed that propranolol significantly upregulated CDK11A and CDK11B. Functional studies demonstrated that knockdown of CDK11 attenuated the pro-apoptotic and cell cycle arrest effects of propranolol and vemurafenib. Mechanistically, propranolol induced G1/S phase arrest and apoptosis without affecting MAPK or AKT pathway reactivation. In a xenograft model, the combination of propranolol and vemurafenib significantly suppressed tumor growth and improved survival. Our study identifies CDK11 upregulation as a novel mechanism by which propranolol reverses vemurafenib resistance, supporting the clinical potential of this drug combination in resistant melanoma. Overall design: Libraries were prepared with the TruSeq Stranded mRNA LT Sample Prep Kit (Illumina) and sequenced on an Illumina HiSeq 2000 platform (paired-end 150 bp). Raw reads were aligned to the human reference genome (GRCh37/hg19) using TopHat (v1.3.3).