The WEE1 inhibitor azenosertib broadly enhances efficacy of antibody-drug conjugates with topoisomerase I and microtubule inhibitor payloads.
Combining azenosertib with ADCs may enhance their efficacy and overcome resistance, but further clinical validation is needed.
Where it sits
this study against the rest of the tesofensine corpusSummary and findings
The study evaluated the WEE1 inhibitor azenosertib in combination with antibody-drug conjugates (ADCs) carrying topoisomerase I or microtubule inhibitor payloads in patient-derived xenografts. Azenosertib enhanced DNA damage and apoptosis, extended response duration, and overcame resistance in these models. Synergistic effects were observed with both types of ADCs, and combinations were well tolerated in vivo.
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 <i>in vivo</i>. These findings position azenosertib as a broadly applicable enhancer of cytotoxic-payload ADCs, offering a promising strategy for patients with advanced solid tumors.
Background
Antibody-drug conjugates (ADCs) have significantly advanced targeted cancer therapy by delivering cytotoxic agents directly to cancer cells. However, resistance to ADCs remains a significant challenge, necessitating strategies to enhance their efficacy. This study explores the potential of combining ADCs with the WEE1 inhibitor azenosertib, hypothesizing that this combination could potentiate the anti-tumor effects by increasing DNA damage and disrupting mitosis.
Methods
The study utilized patient-derived xenografts to evaluate the efficacy of azenosertib in combination with ADCs. The ADCs carried either topoisomerase I inhibitors (TOP1i) or microtubule inhibitor (MTI) payloads. The primary outcomes were the enhancement of DNA damage, apoptosis, and overcoming resistance to ADCs. The study also assessed the tolerability of these combinations in vivo.
Results
Azenosertib enhanced the activity of both free TOP1i agents and TOP1i-based ADCs, such as trastuzumab deruxtecan and sacituzumab govitecan, by increasing DNA damage and apoptosis. It also extended the duration of response and overcame resistance to T-DXd in patient-derived xenografts. Synergistic effects were observed with MTI agents and MTI-based ADCs, leading to exacerbated mitotic defects and prolonged mitotic arrest. All combinations were well tolerated in vivo.
Interpretation
The study suggests that azenosertib could enhance the efficacy of ADCs by increasing their cytotoxic effects and overcoming resistance mechanisms. While the findings are promising, they are based on xenograft models, which may not fully translate to clinical settings. The lack of specific numeric data and statistical analysis in the abstract limits the ability to assess the clinical significance of the findings.
Key findings
- Azenosertib enhanced activity of free TOP1i agents and TOP1i-based ADCs.
- Increased DNA damage and apoptosis were observed.
- Extended duration of response and overcame T-DXd resistance in xenografts.
- Synergistic effects with MTI agents and MTI-based ADCs.
- Combinations were well tolerated in vivo.
Limitations
- Conducted in patient-derived xenografts.
- No specific numeric findings reported.
- Lack of statistical significance data.
- Potential translation issues to human biology.