Combined MDM2 and G2/M checkpoint inhibition induces synergistic antitumor response in gastric signet-ring cell carcinoma

Signet ring cell carcinoma (SRCC) poses a considerable challenge in terms of treatment, given its refractory nature and poor outcomes. Unlike other cancers, SRCC exhibits significant MDM2 copy number gains, with elevated MDM2 expression linked to poor prognosis. MDM2 inhibition induces a morphological transition in SRCC cells by suppressing E-cadherin degradation, which may render these cells vulnerable to a second drug. Using a high-throughput drug screen, our study demonstrated that the combination of MDM2 inhibitors with G2/M checkpoint inhibitors, including WEE1 or CHK1 inhibitors, can elicit a synergistic antitumor response in SRCC cells by inducing DNA damage. Furthermore, pharmacological inhibition of MDM2, WEE1, or CHK1 significantly impeded tumor growth in in vivo mouse models and organoids of SRCC. Collectively, our findings indicate that MDM2 inhibition-induced morphological changes may enhance the efficacy of G2/M checkpoint inhibitors, presenting a promising combined treatment for SRCC.