2X-121/stenoparib——一种在晚期卵巢癌2期临床试验中的新型PARP和tankyrase双重抑制剂——在临床相关药物浓度下阻断WNT信号通路并抑制人结直肠癌细胞系的生长

2X-121 (stenoparib/ E7499) is a novel inhibitor of PARP1/2 (1nM ~IC50) and Tankyrase 1/2 (IC50 ~50nm). As such, 2X-121 impairs DNA repair while simultaneously inhibiting the WNT/ß-catenin oncogenic signaling pathway. 2X-121 has shown durable clinical benefit in a phase 2 study in patients with advanced, platinum resistant and refractory ovarian cancer as a single agent dosed twice daily, regardless of BRCA status. A new protocol is currently enrolling platinum resistant or ineligible ovarian cancer patients to further deepen the clinical understanding of 2X-121 mediated clinical benefit. The clinical experience in ovarian cancer patients has shown benefit in BRCA wt patients- patients who typically do not show durable clinical benefit from first generation PARP inhibitors. These data may suggest that, in addition to PARP 1/2 inhibition, the added activity of 2X-121 inhibiting tankyrase and the WNT pathway may contribute to the therapeutic mechanism of action for 2X-121. Accordingly, 2X-121 may be therapeutically useful as an inhibitor of the WNT pathway for cancers not typically sensitive to PARP 1/2 inhibition. Colorectal cancers are not typically sensitive to PARP1/2 inhibition. However, approximately 80% of colorectal cancers (CRCs) do show mutational activation of the canonical WNT pathway, which may impart resistance to standard chemotherapy. Moreover, WNT pathway activation may also enable a cancer initiating cell/ cancer stem cell-like phenotype enabling the cellular plasticity that often characterizes advanced malignancies. We therefore sought to explore the therapeutic activity of 2X-121 in a panel of CRC cell lines chosen for a spectrum of WNT pathway activating mutations. We show that 2X-121 inhibits growth of multiple colorectal cancer cell lines in monolayer and 3D culture conditions. 2X-121 also inhibits the WNT pathway, stabilizing Axin, reducing activated beta-catenin, and generally blocking WNT pathway activation in CRC cell lines harboring TCF-LEF reporters. The reduction in cell number following 2X-121 treatment may reflect both cytostasis and direct cell killing. Importantly, these effects are evident at clinically relevant drug concentrations for 2X-121. Collectively, these data provide the foundation to explore the clinical potential of 2X-121 in colorectal cancers as well as other cancers where WNT pathway activation is prevalent.