Potent synergy between CHK1/2 inhibitor ACR-368 and the ADC payload topoisomerase I inhibitor: Rationale for ADC + ACR-368 combination therapy

Antibody-drug conjugates (ADCs) enable targeted delivery of cytotoxic payloads to tumor cells, improving the therapeutic index compared with conventional chemotherapy. Topoisomerase I (Topo I) inhibitors are potent ADC payloads that trap the Topo 1-DNA cleavage complex, leading to replication‐fork collapse and tumor cell death. However, this also activates the DNA damage response through CHK1/2-dependent cell cycle checkpoints, attenuating cytotoxicity and enhancing resistance to Topo1-containing ADCs. CHK1/2 inhibition exploits this therapeutic vulnerability, abrogating these checkpoints, increasing replication stress, and hence enhancing the efficacy of Topo I inhibitors across multiple tumor models. Consistent with this, treatment with the potent, selective CHK1/2 inhibitor ACR-368 combined with irinotecan has demonstrated encouraging clinical activity in heavily pretreated patients with sarcomas who had progressed on prior irinotecan therapy. Combined, these data provide a strong rationale for combining ACR-368 with Topo I inhibitor-based therapies. Using the Acrivon Predictive Precision Proteomics (AP3) platform for “Indication Finding”, we previously identified endometrial cancer as a tumor type predicted to be particularly sensitive to ACR-368, which has been shown and is being further evaluated in a Phase 2 registrational trial. In a panel of endometrial cancer cell lines, the combination of ACR-368 with exatecan or SN38 demonstrated synergy in a majority of these, with comparable synergy scores between both Topo I inhibitors. Synergy was observed in both Topo I-sensitive and -resistant lines, supporting the potential to overcome resistance to Topo I inhibitor-based ADCs. To elucidate the pathway mechanisms underlying Topo I inhibitor sensitivity and resistance and the potent, synergistic activity with ACR-368, results from our AP3 Generative Phosphoproteomics approach applied to endometrial cancer will be presented. Combined, these findings demonstrate that CHK1/2 inhibition with ACR-368 synergizes with Topo I inhibitors to enhance cytotoxicity and overcome resistance mechanisms, supporting a mechanistically rational combination strategy with potential to improve the therapeutic benefit of Topo I inhibitor-based ADC therapies.