Combination Therapy with the Epigenetic Drugs JQ1 and SAHA Inhibits PDAC

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and has a high mortality rate, with a five-year-survival of about 5%, underscoring the need for improved therapeutic options. Mazur, Herner, and colleagues showed that, in mouse models of PDAC, the epigenetic drug JQ1, a small-molecule inhibitor of the bromodomain and extraterminal (BET) protein family, blocked tumor initiation and maintenance. This reduction in tumor volume was associated with reduced MYC levels, decreased activation of the pro-survival kinase AKT, and suppressed expression of inflammatory regulators such as phospho-STAT3 and IL6. However, the effect of JQ1 on survival was small, and the mice eventually succumbed to PDAC. SAHA (vorinostat), a small-molecule inhibitor of histone deacetylases (HDAC) that is already approved for human use, was identified as a potential drug that could be combined with JQ1 to improve outcome in PDAC. In a PDAC mouse model, combined treatment with JQ1 and SAHA had a synergistic effect, reducing tumor growth, inducing apoptosis, and increasing overall survival. None of the mice treated with combined JQ1 and SAHA developed tumor relapse or metastases, and dual therapy prevented tumor-associated cachexia. Furthermore, there were no signs of overt systemic toxicity, suggesting this combination as a promising possibility for the treatment of patients with PDAC. As expected, combined treatment led to reduced expression of MYC and HDAC targets and a general decrease in transcription. There was also an increase in the expression of apoptosis-associated genes, with Cdkn1c (encoding p57) being the most synergistically de-repressed gene. Deletion of Cdkn1c reduced apoptosis in tumors treated with JQ1 and SAHA, and partially reversed the effects of combination therapy, indicating that it may be one of the key mediators of the anticancer activity of JQ1/SAHA treatment. Taken together, these results indicate that PDAC is strikingly sensitive to targeting with epigenetic inhibitors and support clinical trials of this therapeutic strategy.

Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 2015;21:1163–71.

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