Abstract A091: The class I selective, oral HDAC inhibitor bocodepsin enhances the response to MAPK pathway inhibitors in multiple tumor types with mutations in MAPK pathway signaling proteins
Authors: Woessner Rich , Hoh Maria , Winkler James , Piscopio Tony , Walker Duncan 
Published: December 2023

Abstract
Activating MAPK pathway mutations, found in &gt;30% of all human tumors, are frequently associated with poor outcomes. Several MAPK pathway targeted drugs are approved but single agent activity is modest, supporting the need for rational targeted combinations to improve outcomes. Multiple studies propose synthetic lethality between Class I HDAC inhibitors and MAPK pathway inhibitors in MAPK pathway mutated cancers, due to a combined effect of inhibiting double-stranded DNA repair and other survival pathways to drive apoptosis. The use of HDACi has been challenged by poor potency, selectivity, safety and convenience, highlighting the need for a better HDACi in the clinic. Bocodepsin, a potent class I-selective oral HDACi, is currently in a phase 1b/2 trial in combination with binimetinib in patients with NRAS mutant melanoma. The clinical profile shows exposure consistent with preclinical activity with strong pharmacodynamic activity at tolerated doses. OKI-005, a bocodepsin analog optimized for in vitro activity, produces the same active metabolite as bocodepsin. To explore the potential for broad application of bocodepsin combinations, we evaluated OKI-005 in combination with the MEK inhibitor binimetinib in a 72H in vitro proliferation screen of 89 cell lines covering a range of tumor types, MAPK pathway mutations, and co-mutations. Net cell killing with the combination vs. single agents was evaluated at clinically relevant doses. Combination activity was observed in tumor types that commonly harbor activating MAPK pathway mutations, including melanoma (6/13, 46%), pancreatic (3/5, 60%), lung (10/22, 45%) and colon (8/13, 62%). Among these, single agent binimetinib activity was observed in only 1/53. The combination response rate in colon cancer models was of note, as single agent MAPK pathway inhibitors are typically inactive in colon cancers. Activity was independent of the activating MAPK pathway mutation: combination activity was observed in lines with KRAS (13/24, 52%), NRAS (8/12, 67%) and BRAF (7/13, 54%) mutations. These findings translated to combinations with other MAPK inhibitors in vitro and in vivo. In vitro, OKI-005 exhibited enhanced activity in combination with KRAS inhibitors and with the ERK inhibitor GDC-0994. 25 of the 89 tumor lines were evaluated in combination with GDC-0994, and the profile of inhibition was identical to that with binimetinib. In vivo, the combination of binimetinib + bocodepsin led to 9/10 regressions in the NRAS mutant melanoma model SK-MEL-2, vs. 0/10 and 2/10 with binimetininb and bocodepsin, respectively. The combination of sotorasib + bocodepsin led to deeper regressions, vs. single agent sotorasib, in the KRAS mutant NSCLC model H358, and greater response in the KRAS mutant NSCLC model H2122. Combination activity was associated with increases in cleaved PARP and p-gH2AX, markers of DNA damage induction and apoptosis. These data demonstrate the potential for bocodepsin to synergize with MAPK pathway inhibitors across multiple indications in tumors that harbor MAPK pathway mutations.
Citation Format: Rich Woessner, Maria Hoh, James Winkler, Tony Piscopio, Duncan Walker. The class I selective, oral HDAC inhibitor bocodepsin enhances the response to MAPK pathway inhibitors in multiple tumor types with mutations in MAPK pathway signaling proteins [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A091.