Abstract 6957: Taking a new approach to treating p53 null endometrial and ovarian cancers by combining chemotherapy with tyrosine kinase inhibitors
Authors: Jamie L. Padilla, Lane E. Smith, Irina V. Lagutina, Mara P. Steinkamp, Kimberly K. Leslie
Journal: Cancer Research (2025)

Abstract Endometrial and ovarian cancers are of the most common gynecologic cancers, and endometrial cancer incidence and mortality rates are rising. The majority of the highest risk forms of these cancers harbor mutations in the central tumor suppressor p53, encoded by the gene TP53. Approximately 30% of mutations such as frame shift alterations, result in a p53 null state as distinguished from the other broad category of p53 mutant tumors that are hotspot single amino acid missense alterations. With the loss of p53-dependent cell cycle checkpoints in p53 null cells, these tumors depend exquisitely on a signaling pathway downstream of p38 MAPK to enforce the G2/M checkpoint by phosphorylating cdc2, the G2/M checkpoint gatekeeper, allowing tumor cells to stop and repair DNA before entering mitosis. Using preclinical cell, organoid and PDX studies we report that adding a tyrosine kinase inhibitor to abrogate the p38 MAPK enforced G2/M checkpoint is synergistic with chemotherapy and results in mitotic catastrophe specifically in p53 null cells. Endometrial p53 null Hec50 and ovarian cancer PDX9 organoids were treated with therapeutically relevant doses of the TKIs erlotinib (an EGFR/MAPK inhibitor) or lenvatinib (primarily targeting VEGFR), paclitaxel alone or the combination of each TKI +paclitaxel and assessed for cell viability using both the CyQuant DNA platform and the Incucyte cell imaging platform. Cells expressing either wild type or missense mutated p53 were used in parallel experiments as comparisons to the p53 null models. Our striking results indicate that the combination of erlotinib and paclitaxel was highly synergistic specifically in p53 null cells with a significant reduction in the IC50 of the paclitaxel when erlotinib was added to the regimen. This result was specific for p53 null models, not for wild type or missense mutated models. Furthermore, the active regimen was erlotinib +paclitaxel, not lenvatinib +paclitaxel, indicating that the effective TKI to achieve synergy must target the EGFR/MAPK pathways, and targeting VEGFR pathways does not produce synergy under these conditions. Studies are now underway in additional cell, organoid and PDX models to validate our initial findings. The impacted kinome is also being assessed to further determine the specific targets of each TKI in the p53 null versus p53 wild type and missense mutated models. By exploring the potential of combining a TKI with chemotherapy specifically for patients with p53 null tumors, we hope to provide a more effective treatment option for this challenging subgroup of patients. Citation Format: Jamie L. Padilla, Lane E. Smith, Irina V. Lagutina, Mara P. Steinkamp, Kimberly K. Leslie. Taking a new approach to treating p53 null endometrial and ovarian cancers by combining chemotherapy with tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6957.