Abstract 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 BRCAwt 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. Citation Format: Louis F. Stancato, Sydney Leohr, Mustapha Moussaif, Mogens Winkel Madsen, Steen Knudsen, Annette Nielsen, Mette Jacobsen, Peter Gimsing, Thomas Jensen, Jeremy R. Graff. 2X-121/ stenoparib - a novel, dual inhibitor of PARP and tankyrase in phase 2 clinical trials in advanced ovarian cancer- blocks the WNT signaling pathway and inhibits growth of human colorectal cancer cell lines at clinically relevant drug concentrations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4576.
Stancato et al. (Fri,) studied this question.