urn:osa:lingual.bio:rec:e33d20a8-457d-47ea-983e-79e53e6a5989@1Propranolol overcomes vemurafenib resistance in melanoma by upregulating CDK11 and inducing cell cycle arrest
Expression profiling by high throughput sequencingSummary
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 β-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.
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urn:osa:lingual.bio:rec:e33d20a8-457d-47ea-983e-79e53e6a5989@1