bims-p53act 2026-01-25 papers

Ecancermedicalscience. 2025 ;19 2011

The prognostic value of L1CAM in association with p53 in high-grade endometrial cancer.

Eduardo Paulino, Guilherme Gomes de Mesquita, Andreia Cristina de Melo.

Endometrial cancer (EC) treatment changed substantially with the introduction of molecular classification. There is a paucity of data regarding the added value of L1CAM in patients with p53 aberrant tumours. The present study aimed to analyse the prognostic value of L1CAM associated with p53 aberrant EC. Patients with EC treated between 2010 and 2016 were retrospectively evaluated. Patients included in this analysis must have reviewed high-grade histologies (endometrioid grade 3, serous, clear cell, carcinosarcoma, mixed and undiffrentiated). Samples were subjected to immunohistochemistry for L1CAM and p53. Recurrence-free survival (RFS) and overall survival (OS) were analysed by the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was performed for multivariable analysis. From 2010 to 2016, 464 patients met the inclusion criteria. Patients with p53 wild type and L1CAM negative (p53wt/L1CAMneg) corresponded to 13.6% (59 patients) of the population, p53 wild type and L1CAM positive (p53wt/L1CAMpos) to 11.7 % (51 patients), aberrant p53 and L1CAM negative (p53ab/L1CAMneg) to 32.9% (143 patients) and aberrant p53 with L1CAM positive (p53ab/L1CAMpos) to 41.8% (182 patients). In univariate and multivariate analysis, compared to patients with p53wt/L1CAMneg, the presence of p53wt/L1CAMpos, p53ab/L1CAMneg and p53ab/L1CAMpos was statistically associated with a worse RFS (HR 2.02; HR 2.20 and HR 2.99, respectively) and OS (HR 2.39; RH 2.31 and RH 2.94, respectively). In the present analysis of a high histological risk population, stages I-IV, we observed that the presence of p53ab/L1CAMpos was associated with a worse RFS and OS when comparing p53wt/L1CAMneg patients. Patients with L1CAMpos had the same worse prognosis as p53ab tumours.

Keywords: L1CAM; endometrial cancer; p53 aberrant

DOI: https://doi.org/10.3332/ecancer.2025.2011

Adv Sci (Weinh). 2026 Jan 20. e13369

Dual Targeting of Mutant p53 and SNRPD2 via Engineered Exosomes Modulates Alternative Splicing to Suppress Ovarian Cancer.

Wei Zhao, Qian Hao, Yu Gan, Jing Tong, Xiaodan Chen, Shuran Tan, Ruiwen Ruan, Yingdan Huang, Mingming Cao, Jun Deng, Tao Han, Getao Shi, Bo Gao, Yu Zhang, Xiang Zhou.

Mutation of the tumor suppressor gene TP53 promotes ovarian cancer progression and therapeutic resistance. Whether mutant p53 (mtp53) regulates alternative splicing and how this regulation can be exploited for cancer therapy remain unclear. Here, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2) as a binding partner of mtp53 is identified. SNRPD2 is highly expressed in ovarian cancer and associated with an unfavorable prognosis. The overexpression of SNRPD2 promotes, whereas its depletion inhibits, the growth and migration of ovarian cancer cells. Mechanistically, mtp53 cooperates with SNRPD2 to facilitate the assembly of the Sm/SMN protein complex, an essential component of the spliceosome, modulating alternative splicing of pre-mRNAs. Specifically, the co-depletion of mtp53 and SNRPD2 reduces the level of OTUD3 oncogenic transcripts while increasing its tumor suppressor counterparts through an exon-skipping event. Moreover, therapeutic engineered exosomes are developed with their surfaces decorated with iRGD and their interiors loaded with siRNAs targeting mtp53 and SNRPD2. These exosomes effectively suppress the growth of ovarian cancer cells and enhance their sensitivity to chemotherapy in vivo. Collectively, this study uncovers that mtp53 and SNRPD2 cooperatively regulate alternative splicing to drive ovarian cancer progression, and co-targeting these two molecules via engineered exosomes represents a potential therapeutic strategy for ovarian cancer.

Keywords: SNRPD2; alternative splicing; engineered exosomes; p53; targeted therapy

DOI: https://doi.org/10.1002/advs.202513369

Genes Chromosomes Cancer. 2026 Jan;65(1): e70100

Molecular Landscape of TP53/RB1 Co-Altered Tumors Uncovers Emerging Therapeutic Vulnerabilities.

Xuetao Li, Meifeng Ye, Xiaomei Huang, Zhong-Yin Huang, Juan Zhu, Zipeng He, Zhuxiang Zhao, Jun Hou, Shuquan Wei.

BACKGROUND: Although TP53 and RB1 co-alterations play critical roles in promoting malignant development and progression, specific inhibitors targeting this co-alteration are lacking. We performed a pan-cancer analysis to characterize the biology of TP53/RB1 co-alterations and identify therapeutic strategies.
METHODS: We analyzed mutation data and copy number variation (CNV) data from 42 371 pan-cancer samples across 26 cancer types from the cBioPortal database. Among them, 2417 tumors with TP53/RB1 co-alterations were used for further analysis. We characterized their epidemiology and molecular biology. Therapeutic vulnerabilities of co-altered tumors were examined using Cancer Cell Line Encyclopedia drug screening datasets.
RESULTS: TP53/RB1 co-alterations occurred in 5.70% of pan-cancer cases but exhibit striking heterogeneity across cancer types. Patients harboring co-alterations had significantly shorter overall survival (OS) in both primary and metastatic settings and poorer response to immune checkpoint inhibitors. Co-altered tumors displayed frequent alterations in chromatin remodeling genes (CREBBP, ARID1A, and KMT2D) and PI3K pathway (PIK3CA and PTEN), but with distinct tissue-specific mutational patterns: EGFR mutations dominated in lung adenocarcinoma (52%), KRAS in pancreatic cancer (88%), and APC in colorectal cancer (77%). Moreover, upregulated genes in co-altered tumors enriched in cell cycle pathways, DNA repair, and neuronal development, whereas immune/inflammatory signaling was suppressed. Critically, drug screening revealed that co-altered tumors showed increased sensitivity to CDK, AURKA, and PI3K/mTOR inhibitors, but resistance to MAPK/ERK pathway inhibitors.
CONCLUSIONS: TP53/RB1 co-alterations define an aggressive cancer subset with dysregulated cell cycle/chromatin pathways and reduced immunotherapy response. Targeting CDK, AURKA, or PI3K signaling offers promising therapeutic strategies.

Keywords: RB1 ; TP53 ; co‐alterations; pan‐cancer; therapeutic vulnerability

DOI: https://doi.org/10.1002/gcc.70100