Inhibition of HDAC3 Induces BRCAness and Potent Synergy with PARP Inhibition in Neuroendocrine Prostate and Small Cell Lung Cancers
Authors: M. Murray, K. Kotlarczyk, G. Hirschfeld, D. Diaz, S. Nagl, K. Devore,T. Wang, PhD, P. Gonzales, S. Gately, PhD
Translational Drug Development, Scottsdale, AZ
Abrstract: HDAC3 is essential for transcriptional repression and is required for the activity of NCOR1 & SMRT co- repressors complexes. Inhibition of HDAC3 results in the suppression of genes responsible for DNA damage repair and maintenance of genomic stability. HDAC3/NCOR1 also play critical roles in tumor metabolism and immune cell biology. GB-3103 is a novel and potent inhibitor of HDAC3 with an IC50 of 0.56nM that was tested for activity against human neuroendocrine prostate (NEPC) and small cell lung cancers (SCLC). RNA-seq analysis of GB-3103 treated human tumor cells revealed induction of BRCAness, inhibition of genes from DNA repair pathways and inhibition of PI3K-AKT1, MYC and p53 signaling. GB- 3103 showed potent in vitro anticancer activity against the human H660 NEPC line, with an IC50 of 28NM, and 21nM against the murine PNEC30 line and potent IC50 of 16nM against NCI-H209 human lung neuroendocrine cancer. Because of the potent induction of BRCAness we used zero interaction potency (ZIP) model to test the activity of the combination of GB-3103 with a PARP inhibitor against human H660 and murine PNEC30 cell lines. These experiments revealed synergy for the combination of PARPI with GB- 3103 in NEPC. GB-3103 was subsequently tested alone and in combination with olaparib in a xenograft model of H660. GB-3103 (TGI=3%) showed minimal activity at the selected dose against H660 compared to single agent olaparib (TGI=67%). However, when combined with olaparib, GB-3103 revealed potent synergy (TGI=96%, p<0.01). In the NCI-H209 human lung neuroendocrine xenograft model, GB-3103 showed robust activity as a single agent (TGI=83%) compared to single agent olaparib (TGI=33%) and single agent talazoparib (TGI=69%). When combined with olaparib, GB-3103 induced synergistic antitumor effect (TGI=99%, p<0.001) when compared to olaparib treatment alone. When combined with talazoparib, GB- 3103 induced synergistic antitumor effect (TGI >100%, p<0.001) when compared to talazoparib treatment alone. Taken together, these data confirm the important role of HDAC3 in neuroendocrine prostate and small cell lung cancers and suggest HDAC3 inhibition by GB-3103 could be an effective approach for patients with neuroendocrine cancers particularly when combined with inhibitors of PARP.
- GB-3103 is a subnanomolar HDAC3 inhibitor.
- RNASeq analysis shows GB-3103 inhibits DNA repair pathway genes, inducing BRCAness, as well as PI3K-AKT1, MYC and p53 genes.
- B-3103 elicits potent single agent anticancer activity in vitro against human and murine neuroendocrine tumor cell lines.
- Combination of GB-3103 with a PARP inhibitor against neuroendocrine cell lines revealed synergy in targeted concentrations using in vitro screens.
- GB-3103 is synergistic with PARP inhibitors in vivo, resulting in significant tumor growth inhibition in H660 neuroendocrine prostate and NCI-H209 small cell lung xenograft models.
- Potent HDAC3 inhibition by GB-3103 could be an effective approach for patients with neuroendocrine cancers.
- Given the potent inhibition of DNA repair pathways, GB-3103 will have utility in enhancing PARP inhibitor activity in homologous repair proficient tumors or in overcoming PARP inhibitor resistance in homologous repair deficient tumors.