What question did this study set out to answer?

April 5, 2026

Abstract 3149: Micronuclei (MN) dynamics in preclinical models and in patient reticulocytes as a pharmacodynamic biomarker for the first in class DNA polymerase theta (PolΘ) inhibitor ART6043

CBColette L BaxterPharma Nord (United Kingdom)TYTimothy A. YapThe University of Texas MD Anderson Cancer Center SUSusanna V. UlahannanOklahoma State University Oklahoma City

Key Points

To evaluate the utility of micronuclei in reticulocytes as a pharmacodynamic biomarker for ART6043, a DNA polymerase theta inhibitor.
Development of the MN-RET assay for assessing micronuclei in reticulocytes.
Sample collection from both preclinical models and patients.
High throughput flow cytometry utilized to quantify micronuclei in reticulocytes.
Increased MN-RET levels observed in preclinical models correlated with tumor regressions.
Patients receiving ART6043 monotherapy showed elevated MN-RET levels.
Combination therapy with ART6043 and olaparib resulted in significantly higher MN-RET levels.

Abstract

Abstract Introduction: ART6043 is a first in class, potent and selective polymerase domain inhibitor of DNA Polθ, a central mediator of the microhomology-mediated end joining (MMEJ) DNA double strand break (DSB) repair pathway. Novel biomarkers are important to demonstrate target engagement of ART6043. Polθ knock out mouse studies highlighted increased levels of MN in mouse reticulocytes (RETs) and normochromatic erythrocytes since MN are a common hallmark of genome instability. Here we describe the utility of an assay designed to monitor MN induction in reticulocytes from both preclinical models and patient samples to evaluate Polθ inhibition. Methods: This analysis builds on the MN-RETs assay, which is traditionally used as a preclinical toxicology assessment (Tometsko et al., 1995). This assay involves fixing whole blood, isolating reticulocytes (specifically in the human assay), and labelling them for nucleic acids to stain any MN. High throughput flow cytometry is then used to quantify the number of reticulocytes with MN. Results: These data demonstrated the utility of MN-RET as a target engagement biomarker for ART6043 in preclinical studies and in the subsequent clinical study (NCT05898399). In preclinical xenograft models ART6043 monotherapy and ART6043 in combination with olaparib induces MN-RET at doses where tumor regressions occurred. The MN-RET data evaluated in the phase 1 trial of ART6043 mirrored the preclinical data. Patients treated with the highest dose of ART6043 evaluated as monotherapy had elevated MN-RETs, while patients treated with ART6043 in combination with olaparib had statistically higher MN-RET levels. This suggests that the combination of two DNA repair pathway inhibitors, targeting separate mechanisms, leads to a synergistic increase in DNA damage. Summary: The increase in MN-RETs observed in patients dosed with ART6043 has demonstrated target engagement of a Polθ inhibitor for the first time in humans. MN-RETs has demonstrated potential utility as a mechanism of action target engagement biomarker for a range of therapeutics targeting different DNA damage repair pathways. References: Tometsko, A. M., Dertinger, S. D., Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3149.

Ask AI

Helpful

Bookmark

View Full Paper