SM08502-Mediated β-Catenin Repression Synergizes with Olaparib to Inhibit Tumor Progression.

PARP inhibitors (PARPi) have reshaped the clinical management paradigm of multiple cancers, but none more than homologous recombination-deficient high-grade serous carcinoma (HGSC) of tubo-ovarian origin. In patients with HGSC that harbor BRCA1/2-mutations, PARPi maintenance therapy after first-line chemotherapy has resulted in significantly prolonged progression-free and overall survival. However, PARPi resistance is a major clinical challenge, and subsequent therapeutic options for patients with resistant disease remain limited. Whereas mechanisms of PARPi therapy have been described, there have been few clinical studies to translate these strategies into overcoming resistance. Elevated WNT signaling and T-cell factor (TCF) transcriptional activity contribute to PARPi resistance; however, directly targeting WNT signaling is challenging due to on-target adverse events. We tested an indirect WNT inhibitor, a dual CDC-like kinase and dual-specificity tyrosine phosphorylation-regulated kinase inhibitor, SM08502 (cirtuvivint), in combination with PARPi in multiple resistant HGSC models. We determined TCF transcriptional activity and differential gene expression with splicing analysis and used multispectral IHC to interrogate the tumor microenvironment. In PARPi-resistant models, SM08502 inhibits WNT/TCF transcriptional activity, reduces cell viability, and induces DNA damage. In addition, using multiple immune-compromised and immune-intact in vivo models of PARPi-resistant disease, SM08502, in combination with olaparib, significantly reduces disease progression, remodels the tumor immune microenvironment, and extends survival. Specifically, tumors treated with the SM08502/olaparib combination exhibit reduced immune-suppressive PD-1 and PD-L1 expression. This study provides strong preclinical evidence that SM08502, in combination with PARPi, may be an effective strategy to overcome PARPi resistance. SIGNIFICANCE: PARPi resistance is a major clinical challenge. Overcoming PARPi resistance will provide patients with therapeutic options. The study shows, in the context of resistant disease, the potential of targeting CDC-like kinase/dual-specificity tyrosine phosphorylation-regulated kinase alone and in combination with PARP inhibitors.