TP53 R248Q

Targeted next-generation sequencing reconfirmed frequent edit errors in both PE2 and PE3b-transfected 697 cells, and it revealed frequent successful edits in HEK293T cells. These observations suggest a requirement for further modification of the PE2 and PE3b systems for accurate editing in leukemic cells.

This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.

Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA)... TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. >

The combination of the BCL2 inhibitor venetoclax (VEN) with hypomethylating agents (e. g. azacytidine, AZA) significantly increased complete remission (CR) rates and prolonged overall survival of adults with Acute Myeloid Leukemia (AML) who were ineligible to intensive chemotherapy. We uncovered the potential combination effects of CPC with VEN in leukemic models of resistance to VEN. Mechanistically, CPC treatment induced impaired mitochondrial metabolism, DNA damage and decreased the expression of proteins related with VEN-resistance in AML, possibly explaining the synergic effects observed between VEN and CPC.

We are currently investigating proteins that mediate RPS19 and RPL5 DSB recruitment. Together, our results support a model whereby altered DNA DSB repair in RPS19- and RPL5-deficient cells may contribute to cancer development in DBA.

When used sequentially with LBS-007, hydroxyurea provided a robust response yielding GI50's between 1 and 3 nM for LBS-007, effectively blocking DNA replication origins (LBS-007) and inducing fork stalls (HU)...Most impressively, the combination of LBS-007 and venetoclax was exponentially enhanced when used in conjunction with ceralasertib (4.8 pM)...Our results identify a unique and potentially efficacious strategy to treat one of the most difficult to treat subtypes of AML. These findings will provide the rationale for potential clinical trials using CDC7 inhibition in p53 mutated or R/R AML.

Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model.

The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.

Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

We have tested our ranking system and new plasmid constructs to engineer the p53 mutants Y220C, R282W and R248Q into wild-type p53 cells and shown that these mutants cannot activate four p53 target genes, mimicking the behaviour of endogenous p53 mutations. This field will continue to rapidly progress, requiring new strategies such as we propose to ensure desired base-editing outcomes.

P1, N=10, Recruiting, Chinese PLA General Hospital | Initiation date: Feb 2023 --> Jul 2023

This mutation analysis represents one of the most robust assessments of longitudinal ctDNA by NGS for TP53 from an MDM2–p53 antagonist trial in liposarcoma. While acquired mutations in TP53 are very common, these data suggest that brigimadlin does not systematically lead to broad acquisition of resistance by inducing alterations in TP53.

We report biomarkers associated with clinical response and resistance to REGN5093 which may help with screening of aNSCLC pts in future combination studies of REGN5093 with other therapies.

P2, N=60, Not yet recruiting, Sun Yat-sen University

YY1 drives PHGDH expression in the context of mutant p53 and promotes bladder tumorigenesis, which preliminarily explains the relationship between high-frequency mutations of p53 and dysfunctional serine metabolism in bladder cancer.

GOF and non-GOF mutp53 were associated with differential prognosis in advanced PDAC. The adverse effect of mutKRAS on OS appeared to be primarily driven by patients with mutCDKN2A. Our results provide new insight that could be helpful for prognostic stratification in clinical practice and for aiding future clinical trial designs.

Thyroid tumors have been occasionally reported in BHD. While most of them are papillary or follicular tumors, only one case of OTC in BHD has been previously reported in the literature [1]. This report underscores the importance of screening for thyroid neoplasms in patients with BHD.

In CRC, non-GOF mTP53 was prevalent in more than half of all cases. Compared to GOF mTP53, predictive biomarkers of response to immune checkpoint inhibitors (TMB and MSI-H/dMMR) were higher in this cohort albeit still relatively rare. Otherwise, differences in molecular signatures between GOF and non-GOF mTP53 did not contain clinically meaningful differences.

This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381.

These results confirm the non-equivalence of p53 mutations in the context of hepatocellular carcinoma and suggest the acquisition of a gain-of-function phenotype for certain mutants. Experiments are ongoing to validate this observation and identify the molecular mechanisms involved in this process.

To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3. APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC.

P1, N=10, Recruiting, Chinese PLA General Hospital | N=20 --> 10

In contrast, TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets. Collectively, our work indicates that NFIA-ETO2 initiates PEL by suppressing gene expression programs of terminal erythroid differentiation and cooperates with TP53 mutation to induce erythroleukemia.

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p < 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML.

TP53 mutation and hepatocellular carcinoma-related pathway may play an important role in the poor prognosis of GAED, which belonging to chromosomally unstable subtype. In addition to anti-HER2 therapy, targeted-TRK and immunotherapy may be the efficient treatments for patients with GAED in the future.

P1, N=20, Recruiting, Chinese PLA General Hospital

Valosin-containing protein (VCP)/p97 or p97 is an AAA+ type ATPase involved in quality control of cellular proteins in normal and transformed cells, especially under cellular stress. Finally, in a tail-vein infused, luciferase transduced, aggressive xenograft model of MOLM13 cells, after AML engraftment, co-treatment for 3 weeks with CB-5339 (50 mg/kg/day, PO) and either venetoclax (30 mg/kg/day, PO) or OTX015 (30 mg/kg/day, PO), as compared to treatment with vehicle or each drug alone, significantly reduced the AML burden and improved median and overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight that CB-5339 induces lethal ER stress in AML cells regardless of the TP53 status, and underscore the promise of CB-5339 treatment alone and in rational combinations in exerting efficacy against AML, including those with high-risk genetic alterations in TP53 or chromosome 3q26 lesions and EVI1 overexpression.

She presented 2 weeks later with worsening neck pain and dyspnea where was admitted to the ICU for airway watch and started on dexamethasone 40 mg with R‐EPOCH chemotherapy...TP53 mutation has been associated with tumor aggressiveness in follicular, poorly differentiated, and anaplastic thyroid cancers and can be synergistic with MYC mutation in aggressive B cell lymphoma. Further research is needed on the role this mutation plays in the pathogenesis of thyroid lymphoma.

ColoScape™ Colorectal Cancer Detection Test is a novel highly-sensitive in vitro diagnostic assay using theqPCR-based multigene panel for the qualitative detection of colorectal cancer-associated gene mutations inliquid biopsy samples. The test targets 61 mutations in 8 genes and 7 methylation markers mostly associatedwith colorectal cancer utilizing our XNA technology which leverages a sequence-specific clamp made by xenonucleic acid (XNA) Target Genes: APC (1309 1367 1450) CTNNB1 (41 45) KRAS (12 13) BRAF 600 TP53 (R273HR175H R248Q) SMAD4 (R361C) PIK3CA (E545K) NRAS G12D Sensitivity for CRC: 88.9% 62.5% for Advancedadenoma Specificity 96%.

ColoScape™ Colorectal Cancer Detection Test is a novel highly-sensitive in vitro diagnostic assay using the qPCR-based multigene panel for the qualitative detection of colorectal cancer-associated gene mutations in liquid biopsy samples. The test targets 61 mutations in 8 genes and 7 methylation markers mostly associated with colorectal cancer utilizing our XNA technology which leverages a sequence-specific clamp made by xeno- nucleic acid (XNA) Target Genes: APC (1309 1367 1450) CTNNB1 (41 45) KRAS (12 13) BRAF 600 TP53 (R273H R175H R248Q) SMAD4 (R361C) PIK3CA (E545K) NRAS G12D Sensitivity for CRC: 88.9% 62.5% for Advanced adenoma Specificity 96%.

In conclusion, we obtained a group of shared neoantigen candidates in esophageal carcinoma and validated the immunogenicity of three novel TP53 neoantigens. These peptides might be potential targets for immunotherapy.

Thus, different TP53 missense mutations contribute differently to cancer progression. Elucidation of the differential impact of distinct TP53 mutations on disease features may make TP53 mutational information more actionable, holding potential for better precision-based medicine.

At the same time, the occurrence of “hot spots” mutations in MCL and FL is also higher than expected. Further studies concerning the type of mutations, their allelic load, and their combination with 17th chromosome lesions in association with disease course are on the way.