bims-p53act 2026-01-18 papers

Cell Oncol (Dordr). 2026 Jan 13. 49(1): 23

Development of an APC and TP53-based duplex sequencing assay to positively predict colorectal cancer response to anti-EGFR therapy.

Mingli Yang, Michael J Schell, Jesse J Salk, Jake Higgins, Michael Hipp, Lance Pflieger, Warren Jack Pledger, Timothy J Yeatman.

PURPOSE: EGFR inhibitor (EGFRi) therapies have been FDA-approved for metastatic colorectal cancer (CRC). However, extended RAS/RAF testing required in the drug labels, identifies only non-responders, and only ~50% of selected patients respond to therapy, suggesting an unmet need to develop additional biomarkers.
METHODS: We previously reported combined mutations in APC and TP53 as a potential positive biomarker to identify EGFRi-sensitive patients. By leveraging the TwinStrand Duplex Sequencing (DS) technology, this study developed an ultrasensitive 6-gene panel DS assay that adds a positive filter for APC(A) and TP53(P) mutations in addition to the negative KRAS(K), BRAF(B), and NRAS(N) mutation filters for EGFRi therapy.
RESULTS: The 6-gene DS assay was analytically validated using reference cell lines (n = 9, individually sequenced to > 3,000x Duplex depth). The assay yielded exceptionally high assay performance on (1) accuracy, (2) sensitivity, (3) specificity and (4) precision. Application to fresh frozen (FF):FFPE paired tissues from 21 CRC patients demonstrates that the ultrasensitive DS assay can accurately detect additional "new" mutations at low allelic frequencies compared to a standard NGS method (13 of the 17 new mutations had < 10% VAF) that may ultimately be responsible for drug resistance. Furthermore, Kaplan-Meier analysis on Duplex-sequenced EGFRi FFPE samples showed that the third-line metastatic CRC patients harboring combined APC and TP53 mutations (AP/APK(N) versus others) tended to have longer TOT (6.65 versus 3.60 months, p = 0.048, n = 29).
CONCLUSION: These data suggest the potential of the 6-gene Duplex Sequencing assay to improve EGFRi patient selection and therapeutic outcomes.

Keywords: APC; Colorectal cancer; Duplex sequencing; EGFR inhibitor; Mutation biomarker; TP53

DOI: https://doi.org/10.1007/s13402-025-01140-y

J Pharm Bioallied Sci. 2025 Dec;17(Suppl 4): S3268-S3270

Evaluation of Circulating Tumor DNA as a Biomarker for Chemoresistance in Colorectal Cancer.

Koduvayur Roopa Lakshmi, Charan Sankar Sankaranarayanan, Raja A S Gogineni, K Afsar Shaheen, Parasharan Peddi.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally. Resistance to chemotherapy, particularly to first-line regimens such as FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), remains a critical barrier to successful treatment.
Methods: This prospective observational study enrolled 96 patients with stage II-IV colorectal adenocarcinoma receiving first-line FOLFOX chemotherapy. Plasma samples were collected at baseline, post-cycle 3, and post-cycle 6 for ctDNA quantification and sequencing of KRAS, NRAS, and TP53 mutations. Radiological tumor response was assessed by RECIST v1.1 criteria. Statistical analysis included ANOVA, Chi-square tests, and logistic regression.
Results: Among 96 patients (mean age 60.3 ± 8.2 years; 58.3% male), 34 (35.4%) exhibited chemoresistance. Baseline ctDNA levels were significantly higher in resistant patients (38.7 ± 10.5 ng/mL) compared to responders (25.4 ± 9.3 ng/mL, P < 0.001). TP53 mutations were more frequent in resistant patients (58.8% vs. 27.9%, P = 0.004). A >20% reduction in ctDNA by cycle 3 was associated with treatment response (OR 4.12, 95% CI 1.76-9.67, P = 0.001). ROC curve analysis yielded an AUC of 0.84 for ctDNA reduction as a predictor of chemoresistance.
Conclusion: Elevated baseline ctDNA levels and persistent TP53 mutations are associated with chemoresistance in colorectal cancer. Early reduction in ctDNA during therapy may serve as a robust predictor of response, supporting its integration into personalized treatment strategies.

Keywords: Biomarker; chemoresistance; colorectal cancer

DOI: https://doi.org/10.4103/jpbs.jpbs_1319_25

J Clin Invest. 2026 Jan 13. pii: e196613. [Epub ahead of print]

T cell receptor-engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models.

Malignant tumors with TP53 mutations exhibit poor therapeutic outcomes and high recurrence rates. T cell receptor (TCR)-based T cell therapy shows great promise for targeting intracellular cancer neoantigens. However, the immunogenic potential of TP53 hotspot mutations remain poorly characterized. Here, we identify a immunogenic neoantigen derived from the recurrent TP53R248Q mutation, presented by the prevalent Human Leukocyte Antigen (HLA)-A*11:01 allele. Additionally, we isolated a TP53R248Q reactive TCR that specifically recognize the TP53R248Q mutation without any discernable cross-activity to cognate wild-type TP53 or other TP53 mutants at the same codon position. Functional characterization revealed that TP53R248Q TCR-T cells exhibited selectively cytotoxicity against tumor cells expressing both TP53R248Q mutation and HLA-A*11:01 in vitro. Importantly, the adoptive transfer of TP53R248Q TCR-T cells exhibited significant anti-tumor activity in a clinically relevant patient-derived xenograft (PDX) model engrafted with TP53R248Q/HLA-A*11:01 positive human tumor tissues. Collectively, our study validates the immunogenicity of the TP53R248Q hotspot mutation and provides a TCR with high therapeutic potential for the development of T cell therapies targeting TP53R248Q/HLA-A*11:01 positive cancers.

Keywords: Cancer immunotherapy; Immunology; Oncology; p53

DOI: https://doi.org/10.1172/JCI196613

MedComm (2020). 2026 Jan;7(1): e70584

Characterization of Korean Colorectal Cancer Reveals Novel Driver Gene and Clinically Relevant Mutations.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths worldwide, characterized by genomic heterogeneity arising from ethnic and interindividual differences. Producing region-specific data to characterize ethnic-specific somatic mutations is essential for advancing CRC research. Additionally, accurate somatic mutation detection requires paired tissue analyses to account for interindividual diversity. This study aims to highlight the importance of ethnic diversity in shaping CRC's genomic landscape and emphasize the necessity for region-specific data to refine diagnostic and therapeutic approaches. This study emphasizes the need for region-specific data by analyzing an unprecedented 197 paired samples from the Korean CRC cohort through whole-genome sequencing. We identified 78 potential driver genes. Notably, CBWD5, LRRIQ3, TRIM64B, SPINK5, and ZNRF2 were linked to recurrence, presenting potential therapeutic targets. Our analysis revealed 30 mutational hotspots, with significant variants in KRAS (25%, G12A, G12D, G12V), MAP1A (12%, V2300G), and TP53 (8%, R175H). We identified a significant co-occurrence between KRAS 12 mutation and PIK3CA 545 mutation. Our findings demonstrate potential driver genes and mutational hotspots associated with CRC patient, characterizing the mutational landscape related to clinical characteristics. Significantly advancing our understanding of CRC's heterogeneous nature, this study lays a solid foundation for devising more efficacious management strategies.

Keywords: colorectal cancer; microsatellite instability; mutational hotspots; tumor mutational burden; whole‐genome sequencing

DOI: https://doi.org/10.1002/mco2.70584