Abstract 4205: Direct measurement of TA repeat expansions significantly outperforms MSI-H status as a predictor of sensitivity to the novel WRN inhibitor MOMA-341

MOMA-341, first disclosed herein, is a novel, potent, and selective clinical stage small molecule inhibitor of the Werner RecQ like helicase (WRN) that acts through an allosteric, ATP-competitive binding mechanism and covalent ligation of WRN at cysteine 727. Consistent with WRN genetic depletion in MSI-H models, MOMA-341 induces DNA damage, cell death, and tumor regressions in mismatch-repair deficient (dMMR)/microsatellite instability high (MSI-H) models but has no effect in MSS tumor models or cell lines derived from normal tissues. MSI-H status, defined by loss of MMR proteins or using short read sequencing algorithms, correlates with MOMA-341 single agent activity in preclinical models but is an imperfect predictor, with a 62% Positive Predictive Value (PPV) and a 38% False Positive Rate (FPR) (N=40 MSI, 8 MSS), consistent with rates reported with other WRN inhibitors. In contrast, direct measurement of genome-wide TA repeat expansions, the substrate of WRN helicase and a feature of many MSI-H tumors, by long read sequencing produces a near-perfect prediction of sensitivity to WRN inhibition across a large cohort of preclinical tumor models spanning colorectal, gastric, and endometrial lineages (N= 36 MSI-H, 8 MSS). Long-read sequencing provides optimal insight across the genome for this purpose as it can discriminate the location, total length, and allelic heterogeneity of TA repeat expansions, whereas the TA repeat expansions that dictate WRN sensitivity are largely invisible to commonly used short read sequencing methods. While MSI-H tumors with highly expanded TA repeat regions were quite sensitive to MOMA-341, incomplete single agent antitumor activity was observed in tumors with lower levels of TA repeat expansion. However, these tumor responses could be converted to regressions when MOMA-341 was combined with chemotherapies such as irinotecan. This work demonstrates clearly that direct and specific measurement of the TA repeats that serve as a WRN helicase substrate is feasible, quantifiable and results in near perfect prediction of MOMA-341 anti-tumor activity in preclinical models, thereby successfully matching the relevant biology with pharmacologic response. Guided by this work, TA repeat expansions will be assessed in patient tumors within the upcoming Phase 1 clinical trial of MOMA-341 in dMMR/MSI-H tumors to better inform patient selection and the choice of single agent or combination dosing regimens. Citation Format: Anthony Tubbs, Javad Golji, Meredeth McGowan, Theresa Baker, Giulia Bottoni, Erin Brophy, Xin Cindy Yang, Haley Amemiya, Momar Toure, John R. Butler, Haoxuan Wang, Cen Gao, Timothy Guzi, Peter Hammerman, Erica Evans, Allison Drew. Direct measurement of TA repeat expansions significantly outperforms MSI-H status as a predictor of sensitivity to the novel WRN inhibitor MOMA-341 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4205.