MDM2拮抗剂ASTX295与Olaparib联合用作BRCA2突变、TP53野生型实体瘤的新型治疗方案

p53, encoded by the TP53 tumor suppressor gene, is a critical regulator of the cellular response to stress such as DNA damage and oncogenic signaling. p53 triggers the transcriptional program that dictates cell-fate decisions, including cell cycle checkpoint activation, senescence, and apoptosis. In tumors with functional p53, reactivation of TP53 transcriptional activity has emerged as an attractive therapeutic approach to promote cancer cell death. Therefore, inhibition of MDM2, the key negative regulator of p53, has been an attractive target to achieve this strategy. ASTX295 is a selective small molecule antagonist of the p53/MDM2 interaction, resulting in p53 stabilisation. Whilst the efficacy of MDM2 antagonists as monotherapy has been modest, there is a strong rationale for MDM2-combination therapies blocking DNA repair or inducing DNA damage to potentiate p53-mediated apoptosis. We identified components of DNA repair pathways including PARP1 as strong sensitizers to ASTX295 in a genome-wide drug-CRISPR screen. PARP inhibition results in DNA damage when single strand breaks are converted into double strand breaks during S-phase, leading to the accumulation of unresolved DNA damage and triggering checkpoint activation. PARP inhibitors have been shown to induce p53 activation and, in turn, promote p21-mediated cell cycle arrest. In the presence of an MDM2 antagonist, this excessive genotoxic stress combined with sustained p53 activation leads to increased apoptosis, offering a more durable response than PARP inhibition alone. We demonstrated the combinatorial interaction of ASTX295 with Olaparib in drug combination screens, and our proprietary biomarker discovery pipeline, PRIME, identified significantly enriched combination synergy and reduced viability in BRCA2-mutant solid tumor cell lines. We established that synergistic cell death is driven by elevated p53 activity for the combinatorial administration of ASTX295 with Olaparib, particularly in BRCA2-mutant/TP53-wild-type solid cancer cell lines. In vivo, using both cell line- and patient-derived BRCA2-mutant/TP53 wild-type xenograft models, we showed superior anti-tumor activity for the combination compared to single agents, resulting in prolonged control of tumor growth and regressions at well tolerated doses. Taken together, our data provide a strong rationale for combining ASTX295 with PARP inhibitors such as Olaparib in patients with TP53-wild-type/BRCA2-mutant solid tumors.