ArticleiScience2026
The WEE1 inhibitor azenosertib broadly enhances efficacy of antibody-drug conjugates with topoisomerase I and microtubule inhibitor payloads.
Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Antibody-drug conjugates (ADCs) have transformed targeted cancer therapy, yet strategies to overcome resistance and enhance efficacy remain needed. Since ADCs exert anti-tumor effects via DNA damage or mitotic disruption, combining them with WEE1 inhibitors represents a rational approach. We investigated the selective WEE1 inhibitor azenosertib in combination with ADCs carrying topoisomerase I inhibitor (TOP1i) or microtubule inhibitor (MTI) payloads. Azenosertib enhanced the activity of free TOP1i agents and TOP1i-based ADCs (trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan), increasing DNA damage and apoptosis, and extended the duration of response while overcoming T-DXd resistance in patient-derived xenografts. Synergistic effects were also observed with MTI agents and MTI-based ADCs (mirvetuximab soravtansine, tisotumab vedotin, and enfortumab vedotin), associated with exacerbated mitotic defects and prolonged mitotic arrest. All combinations enhanced efficacy and were well tolerated
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