Activating RAS pathway mutations are found in >30% of human tumors, and often associated with poor outcomes. While RAS-pathway targeted drugs have been approved, their activity as single-agents remains modest, supporting the need for rational targeted combinations to improve patient outcomes. Multiple studies have proposed a chemical synthetic lethality between Class I histone deacetylase inhibitors (HDACi), and RAS-pathway inhibitors in RAS-pathway mutated models. This synthetic lethality occurs due to a combined effect to inhibit double-stranded (ds) DNA repair and other survival pathways to drive apoptosis and tumor regressions. The use of HDACi in solid tumors and combinations has been challenged by poor potency, selectivity, safety and convenience, highlighting the need for a better HDACi in the clinic. OKI-179, a novel largazole derivative, is a potent, Class I-selective, oral HDACi that has completed Ph 1 clinical trials in patients with solid tumors. The clinical profile shows the potential to achieve exposure consistent with preclinical activity with strong pharmacodynamic activity at tolerated doses, supporting the development of OKI-179 in solid tumor combinations. Here we show synergistic activity of combining OKI-179 with the MEK inhibitor binimetinib (bini) or bini + RAF-inhibitor encorafenib (enco/bini) in both CDX and PDX models of NRAS-mutated melanoma and BRAF-mutated colorectal cancer (CRC). In vitro, combining OKI-179 with bini in SKMEL-2 NRASMT melanoma cells shows strong synergy, inducing a significant increase in cell death compared to single agents at clinically achievable drug concentrations. This activity was associated with a significant increase in gH2AX, a marker of ds DNA breaks, and apoptosis as measured by cleaved PARP. The activity of this combination was further investigated in vivo in established PDx models of NRAS-mutant melanoma, MEL278 and MM415. As single agents, both bini (3.5 mg/kg PO bid,21 d) and OKI-179 (80 mg/kg PO; 5/wk x 3 wk), doses that mimic the clinical exposure of these molecules, showed modest tumor growth inhibition (TGI). Combining bini and OKI-179 induced significantly greater TGI, including regression in 28-50% of the tumors, as compared to 0-6% for bini alone. A similar outcome was also observed in HT29 tumors (BRAFmt CRC) where the combination of OKI-179 and enco/bini showed regression in 50% of tumors, compared to 0% for OKI-179 or enco/bini alone. This supports the potential for additive efficacy of HDACi combined with RAS-pathway inhibitors across RAS-pathway mutations and tumor types. No additivity was observed in only one model (CRC563 - BRAFmt). These data show the potential for OKI-179 to synergize with RAS-pathway inhibitors across multiple indications. To investigate, a Phase1b/2 trial of OKI-179 with binimetinib in NRAS melanoma will initiate in early 2022.

Citation Format: Richard Woessner, Patrice Lee, Eric Brown, Duncan H. Walker, James Winkler, Tony Piscopio. Theclass Iselective, oral HDAC inhibitor OKI-179 increases tumor regressions when combined with the MEK inhibitor binimetinib inmodels of NRAS melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB204.