bims-p53act 2026-04-26 papers

Mod Pathol. 2026 Apr 21. pii: S0893-3952(26)00048-7. [Epub ahead of print] 101005

Copy Number-Low/TP53 Mutated Endometrial Cancer With Wild Type p53 Immunoexpression: Implications for Risk Stratification and Management When Using Next Generation Sequencing for Molecular Classification.

Joseph T Rabban, Rebecca J Wolsky, Neslihan Kayraklioglu, Kurtis D Davies, Dara L Aisner, W Patrick Devine.

Endometrial cancers with a Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased risk for adverse outcome, meriting maximal adjuvant therapy. In contrast, the prognosis associated with a TP53 mutation that co-exists with a POLE mutation or microsatellite instability aligns with that of ultramutated or hypermutated cancers, respectively. Herein we characterize a rare molecular sub-class of endometrial cancers defined by TP53 mutation but low burden of CN alterations, wild type p53 immunoexpression (IHC) and low TP53 variant allele frequency (VAF, median 13%, maximum 47%). Among 723 consecutive endometrial cancers prospectively classified using next generation sequencing (NGS), 16 (2.2%) were CN-Low/TP53-mutated / p53 wild type IHC. Two additional cases were identified in a separate retrospective cohort of 32 recurrent low grade early-stage endometrial cancers, bringing the total to 18 cases. They affected post-menopausal patients, exhibited low grade endometrioid histotype and were mostly confined to the uterus without lymphovascular space invasion. The recurrence rate was 6.25% (1/16) in the prospective cohort and none died, placing their prognosis closer to that of CN-Low than CN-High cancers. We conclude that NGS-based TCGA classification of TP53-mutated, POLE-wild type, microsatellite stable endometrial cancers with TP53 VAF <50% requires further evaluation by CN analysis and/or p53 IHC to detect this rare molecular category. Immunohistochemistry-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases as the p53 IHC pattern is wild type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on co-existing molecular alterations.

Keywords: TP53; endometrial cancer; molecular classification

DOI: https://doi.org/10.1016/j.modpat.2026.101005

NPJ Precis Oncol. 2026 Apr 20. pii: 159. [Epub ahead of print]10(1):

Multi-omics analysis reveals the key role of STIL in Li-Fraumeni syndrome and osteosarcoma.

Yu Qiao, Jincen Hao, Fahu Yuan, Anna Curto-Vilalta, Long Tang, Rüdiger von Eisenhart-Rothe, Florian Hinterwimmer.

Li-Fraumeni syndrome (LFS), driven by germline TP53 mutations, confers a markedly elevated risk of osteosarcoma (OS), yet the mechanisms beyond TP53 remain insufficiently defined. By integrating multi-omics analyses and in vitro validation, we identify SCL-interrupting locus (STIL) as a pivotal hub linking LFS to OS progression. We reveal that STIL negatively regulates p53 protein stability in a manner independent of TP53 mutation status, indicating that STIL can promote tumorigenesis by dampening p53 pathway activity and stability. Importantly, STIL displays genetic-context-dependent oncogenicity: it supports stemness across OS models, but more strongly drives invasion and metastatic potential in TP53-mutant backgrounds. Specifically, STIL is highly expressed in a population of high-stemness malignant cells (Pro-OSCs), where it maintains stemness and promotes bone destruction by activating PTN-NCL and FN1-CD44 pathways, while simultaneously remodeling the immune microenvironment via MIF and APP signaling to evade immune surveillance. Additionally, WEE1 inhibitors may represent a targeted vulnerability in STIL-high OS. In summary, the relationship between TP53 and STIL is not a simple linear upstream-downstream cascade, but reflects a highly context-dependent regulatory dynamic. STIL exerts oncogenic effects by regulating p53 stability and driving a "stemness-invasive" phenotype in the context of TP53 mutations. This also provides novel biomarkers and intervention targets for precision therapy.

DOI: https://doi.org/10.1038/s41698-026-01432-y

Biochem Biophys Res Commun. 2026 Apr 16. pii: S0006-291X(26)00523-1. [Epub ahead of print]819 153759

p53-R248W evades doxorubicin mediated cell death through collective alteration in TOP2A and CYP1A1 genes in cancer cells.

Megha Mehrotra, Priti S Shenoy, Asmita Sakpal, Sourav Chakraborty, Pritha Ray.

BACKGROUND: Doxorubicin alone or in combination is widely used as first- or second-line chemotherapy in multiple solid tumors. Yet poor overall/progression-free survival and high mortality reflect the inherent Dox-resistance. Such resistance significantly limits the response to anthracycline-containing regimens. Frequent occurrence of TP53 mutations across cancers suggests that mutant-p53 may drive selective chemoresistance towards first- and second-line chemotherapeutics but the underlying mechanism remains inadequately explored.
METHODS: p53 hotspot mutations-R248W, R273H, R175H, R282W and wtp53 were overexpressed in p53-null ovarian (SKOV3) and gastric (KATOIII) cells. R248W mutant was also expressed in p53-null murine breast cancer (4T1) cells. MTT assay, immunoblotting and qPCR were used to assess drug sensitivity, apoptosis, autophagy and gene expression. Flow cytometry and immunofluorescence was used to assess cellular and nuclear doxorubicin levels.
RESULTS: p53-mutant expressing cells showed varied responses to cisplatin and doxorubicin. p53-R248W cells were sensitive to cisplatin but highly resistant to doxorubicin as measured by MTT assay and absence of PARP cleavage in multiple cancer cells. All mutants and wtp53 displayed differential degree of doxorubicin efflux. Doxorubicin-resistant p53-R248W SKOV3 cells could retain the drug, possibly due to decreased ABC transporter levels. Reduced BAX and TOP2A and hyperactivated CYP1A1/A2 levels were observed with doxorubicin-treatment in p53-R248W expressing ovarian, gastric and breast cancer cells.
CONCLUSION: p53-R248W confers selective doxorubicin resistance to multiple cancer cells through TOP2A suppression and CYP1A1/A2 overexpression. These findings highlight the mutation specific mechanism of doxorubicin resistance that might result in poor response and needs to be considered during treatment plan.

Keywords: Chemoresistance; Doxorubicin; Gastric cancer; High-grade serous ovarian cancer; Mutant p53

DOI: https://doi.org/10.1016/j.bbrc.2026.153759

Front Oncol. 2026 ;16 1754873

Eprenetapopt in combination with carboplatin in high-grade ovarian and triple negative breast cancer cell lines with acquired resistance to olaparib.

Begoña Pineda, Juan Jose Martinez-Pretel, Paloma Sanchez-Serrano, Stergios Boussios, Maria Rodrigo-Faus, Martín Pérez-Leal, Elena Obrador, Javier Perea, J Alejandro Perez-Fidalgo.

Background: High-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) frequently exhibit mutations in DNA damage response (DDR) genes, as BRCA1, BRCA2 and TP53, which are associated with chemotherapy sensitivity. Olaparib, a PARP inhibitor, provides the greatest clinical benefit as maintenance therapy in HGSOC-particularly in tumors with BRCA1/2 mutations or broader homologous recombination deficiency (HRD)-whereas benefit in HRD-negative disease is limited. Eprenetapopt (APR-246) restores wild-type p53 function in tumor cells with TP53 mutations. This study investigates the potential of combining eprenetapopt with carboplatin to overcome resistance to the PARP inhibitor (PARPi) olaparib in HGSOC and TNBC cell lines.
Methods: As preclinical models, human ovarian cancer cell lines (HGSOC) (PEO1, Kuramochi) and a triple-negative breast cancer cell line (MDA-MB-231) were utilized as parental lines to generate their respective olaparib-resistant cell lines (PEO1R, Kuramochi-R, MDA-MB-231-R) by exposing the cells to increasing doses of olaparib. Cell viability, apoptosis and cell cycle progression, were assessed using MTT assays and Annexin V assay and propidium iodide staining, respectively. The Chou-Talalay method was used to calculate the combination index (CI) for drug synergism.
Results: Olaparib-resistance was confirmed in both HGSOC and TNBC cell lines, as they exhibited significantly higher IC50 values compared to their respective parental lines. Moreover, the olaparib-resistant cells exhibited cross-resistance to carboplatin. Remarkably, the combination of eprenetapopt with carboplatin showed a synergistic effect in both parental and resistant cell lines, reducing tumor cell viability and demonstrating synergistic interaction compared with single agents. Combinatorial treatment also significantly increased apoptotic cell population in parental HGSOC and TNBC cell lines as well as in MDA-MB-231-R olaparib-resistant cells. Cell cycle analysis revealed that carboplatin mainly induced a significant increase in S or G2/M phase accumulation and a reduction in G1-phase cells, with eprenetapopt having a minimal additional impact.
Conclusions: Combining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib-resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross-resistance in TP53 mutant HGSOC and TNBC cell lines. Although further studies are needed to elucidate the molecular mechanisms underlying the synergistic effect, here we point out the combination of eprenetapopt and carboplatin as a potential therapeutic strategy to address olaparib resistance in HGSOC and TNBC patients.

Keywords: carboplatin; eprenetapopt; high grade serous ovarian cancer; olaparib; synergism; triple negative breast cancer

DOI: https://doi.org/10.3389/fonc.2026.1754873

NPJ Genom Med. 2026 Apr 18. pii: 22. [Epub ahead of print]11(1):

Low-penetrance TP53 variants are mainly hypomorphic: an underestimated issue with high clinical significance.

Lea Rodriguez, Bernard Leroy, Franck Toledo, Julianne Susanne Funk, Thorsten Stiewe, Panagiotis Baliakas, François Delhommeau, Thierry Soussi.

Missense mutations that inactivate p53 are common in cancer. LiFraumeni syndrome, which is linked to early-onset cancer, is caused by germline mutations in TP53. Full-penetrant, inactive variants have garnered great attention, whereas low-penetrant variants are less well understood despite their clinical importance. This study systematically leveraged the 2025 UMD_TP53 database to identify missense variants that exhibit a statistically skewed germline-versus-somatic ratio (GVSr). Unlike classic hotspots that are equally prevalent in somatic and germline settings, these variants were disproportionately found in the germline, suggesting they act as low-penetrance variants with insufficient potency to drive tumorigenesis as single somatic events. To define the biological basis of LPVs, we integrated functional data from multiplexed assays of variant effects, tumor cell transcriptome analyses and computational predictive tools. This characterization revealed that these high-GVSr p53 variants consistently retain intermediate transcriptional activity and growth-suppressive function, classifying them distinctively as hypomorphic alleles rather than loss-of-function mutants. Our findings highlight the complexity of TP53 variant effects and underscore the importance of refined functional classification. Recognizing and accurately characterizing hypomorphic variants associated with low-penetrance cancer risk are essential for precision oncology, as they will improve genetic counseling, risk stratification, and tailored surveillance strategies for individuals with TP53 mutations.

DOI: https://doi.org/10.1038/s41525-026-00568-x

Chin J Nat Med. 2026 Apr;pii: S1875-5364(26)61172-7. [Epub ahead of print]24(4): 414-426

Targeting of MARK2, but not other MARKs, suppresses TNBC progression by inhibition of the mutant p53-driven signaling pathway.

Min Zhang, Xilong Zhu, Mengqian Cui, Yinan Guan, Yong Zhang, Stephen J Weiss, Jun Chen, Yongzhong Yao, Rong Fu, Zhaoqiu Wu.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study, we demonstrate that elevated expression of microtubule affinity-regulating kinase 2 (MARK2), but not other MARK family members (MARK1, MARK3, and MARK4), correlates with poor prognosis in TNBC patients. Silencing MARK2 impairs TNBC progression via inhibition of mutant p53 (mutp53) signaling. In contrast, silencing any of the other three MARKs either enhances or does not affect TNBC cell growth or migration and has no impact on mutp53 expression. Notably, direct knockdown of mutp53 recapitulates the effects of MARK2 ablation in TNBC cells, further supporting a functional linkage. Moreover, ectopic expression of either wild-type (WT) MARK2 or its kinase-dead (KD) mutant enhances mutp53 signaling and promotes TNBC progression; however, MARK2 overexpression does not alter wild-type p53 (wtp53) expression or cell growth in luminal breast cancer cells. Significant inverse correlations are also observed between the expression levels of MARK2, THBS1, or HBEGF (two direct target genes of mutp53) and both overall and disease-free survival in TNBC patients harboring mutTP53, whereas no such association exists between MARK2 and survival in breast cancer subtypes expressing wtTP53. MARK2 is predominantly localized in the nucleus of TNBC cells, where it interacts with and stabilizes mutp53 through its UBA and Spacer domains. Consistent with this, MARK2-ΔUBA or MARK2-ΔSpacer mutant proteins fail to bind mutp53 or sustain its signaling, thereby acting as dominant-negative inhibitors that suppress TNBC progression. Collectively, our findings indicate that suppressing MARK2 expression, rather than inhibiting its kinase activity, may represent an effective therapeutic strategy for TNBC with mutTP53.

Keywords: Dominant-negative MARK2; MARK2; THBS1 and HBEGF; TNBC progression; mutp53

DOI: https://doi.org/10.1016/S1875-5364(26)61172-7