Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma.,Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T).,We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma.,The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.,Thirty-four patients were evaluable for one-year PFS rate.,Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%.,In phase I, there was no dose-limiting toxicity.,HCQ 600 mg orally twice daily with D+T was the RP2D.,The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%).,The complete RR was 41% and median overall survival (OS) was 26.5 months.,In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.,HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate.,There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy.,In this difficult-to-treat population, the RR and PFS were encouraging.,A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.
Targeting CDK4/6 shows great promise in the treatment of many solid cancers, including melanoma.,This study has uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53.,In melanoma, palbociclib activates p53 via modulating PRMT5-dependent alternate MDM4 pre-mRNA splicing, which results in a robust decrease in MDM4 protein expression.,Loss of palbociclib regulation of the PRMT5-MDM4 axis leads to drug resistance.,Dual inhibition of CDK4/6 and PRMT5 potently suppresses melanoma tumor growth and is well tolerated in vivo.,Our findings not only have immediate implications for the advancement of CDK4/6 inhibition for treating melanoma, but also more generally offer insights into CDK4/6 mechanism of action.,Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation.,We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity.,By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation.,In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib.,Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance.,Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance.,Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53.,Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy.,Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.