Abstract 2303: The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models

Abstract

Abstract Introduction: The WEE1 tyrosine kinase is activated upon DNA damage and regulates the G2-M and S phase cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treating cancer. Debio 0123 is a WEE1 specific inhibitor previously shown to sensitize cancer cells to DNA damaging agents which is currently being assessed in combination with carboplatin in patients with advanced solid malignancies. Small cell lung cancer (SCLC) is an aggressive disease with poor clinical outcomes that carries a high mutational burden and genomic instability. Here we investigated the ability of Debio 0123 to enhance SCLC response to standard of care (SOC) DNA damaging agents carboplatin and etoposide in vitro and in vivo. Methods: SCLC cell lines were treated with Debio 0123 alone or in combination with etoposide or carboplatin in vitro and apoptosis assessed by flow cytometry. In vivo SCLC patient derived- or cell line derived-xenograft (PDX or CDX, respectively) models were treated with Debio 0123 orally in combination with either carboplatin or etoposide alone or as a triple combination. Tumor growth inhibition was assessed over 3 cycles of treatment and tolerability of the combinations evaluated by monitoring body weight changes. Results: Debio 0123 synergized with carboplatin and etoposide in vitro leading to a significant increase in the induction of apoptosis. Additionally, Debio 0123 significantly improved the tumor growth inhibitory effect of etoposide and carboplatin in both PDX and CDX models of SCLC in vivo. Triple combination of carboplatin, etoposide and Debio 0123 was well tolerated at therapeutically relevant dosing and resulted in significantly improved tumor response when compared to carboplatin and etoposide treatments alone or to the double combination. Conclusions: Taken together these results highlight that inhibiting WEE1 with Debio 0123 significantly improves tumor response to SOC DNA damaging agents in models of SCLC, providing the foundation for future clinical exploration of Debio 0123 in SCLC. Citation Format: Luke Piggott, Anne Vaslin-Chessex, Noemie Luong, Benjamin Tschumi, Gregoire Vuagniaux. The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2303.