Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer.

OBJECTIVES: To investigate the pattern of first recurrence of disease in patients with endometrial cancer according to molecular classification, and to assess the independent role of molecular profiling in each type of failure. METHODS: Retrospective single-center study including patients diagnosed with endometrial cancer stage I-IVB (International Federation of Gynecology and Obstetrics 2009) between December 1994 and May 2022, who underwent primary surgical treatment and had a complete molecular profile. First recurrence was classified as isolated or multiple, and as vaginal, pelvic, peritoneal, nodal, and distant according to its location. The log-rank test and univariate and multivariate adjusted Cox regression models were used for comparison between groups. RESULTS: A total of 658 patients were included. Recurrence was observed in 122 patients (18.5%) with a recurrence rate of 12.4% among mismatch-repair deficient tumors, 14.5% among non-specific molecular profile, 2.1% among POLE-mutated, and 53.7% among p53-abnormal tumors. Recurrences were found to be isolated in 80 (65.6%) and multiple in 42 (34.4%) patients, with no differences in molecular subtype (p=0.92). Patients with p53-abnormal tumors had a recurrence mainly as distant (28.4%) and peritoneal (21.1%) disease, while patients with non-specific molecular profile tumors presented predominantly with distant failures (10.3%), and mismatch-repair deficient tumors with locoregional recurrences (9.4%).On multivariate analysis, p53-abnormal molecular profile was the only independent risk factor for peritoneal failure (OR=8.54, 95% CI 2.0 to 36.3). Vaginal recurrence was independently associated with p53-abnormal molecular profile (OR=6.51, 95% CI 1.1 to 37.4) and lymphovascular space invasion. p53-abnormal and non-specific molecular profiles were independent predictors for distant recurrence (OR=3.13, 95% CI 1.1 to 8.7 and OR=2.35, 95% CI 1.1 to 5.0, respectively), along with lymphovascular space invasion and high-grade tumors. Molecular profile was not independently associated with pelvic and nodal recurrences. CONCLUSIONS: Endometrial cancer featured different patterns of recurrence depending on the molecular profile. p53-abnormal molecular profiling was the only independent risk factor for peritoneal relapse, while non-specific molecular profile showed a strong association with distant failures.

MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists.

Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL-based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.

Genomic Validation of Endometrial Cancer Patient-Derived Xenograft Models as a Preclinical Tool.

Endometrial cancer (EC) is the second most frequent gynecological cancer worldwide. Although improvements in EC classification have enabled an accurate establishment of disease prognosis, women with a high-risk or recurrent EC face a dramatic situation due to limited further treatment options. Therefore, new strategies that closely mimic the disease are required to maximize drug development success. Patient-derived xenografts (PDXs) are widely recognized as a physiologically relevant preclinical model. Hence, we propose to molecularly and histologically validate EC PDX models. To reveal the molecular landscape of PDXs generated from 13 EC patients, we performed histological characterization and whole-exome sequencing analysis of tumor samples. We assessed the similarity between PDXs and their corresponding patient's tumor and, additionally, to an extended cohort of EC patients obtained from The Cancer Genome Atlas (TCGA). Finally, we performed functional enrichment analysis to reveal differences in molecular pathway activation in PDX models. We demonstrated that the PDX models had a well-defined and differentiated molecular profile that matched the genomic profile described by the TCGA for each EC subtype. Thus, we validated EC PDX's potential to reliably recapitulate the majority of histologic and molecular EC features. This work highlights the importance of a thorough characterization of preclinical models for the improvement of the success rate of drug-screening assays for personalized medicine.