TP53 R273H

Mutational hotspots are a recurrent feature in both genes which, due to positive selection during tumorigenesis, can be potentially exploited by targeted treatments, as has been demonstrated by the US Food and Drug Administration (FDA)-approved PI3K inhibitor alpelisib in advanced hormone-receptor positive (HR+) breast cancer... The AGENA ClearSEEK PIK3CA and TP53 Panels combine low hands-on time requirements with accurate data assessment, and provide a reliable tool for clinical trial evaluation of known actionable PIK3CA mutations and response to PI3K inhibitors in breast cancer, as well as for investigating the oncogenic activities of TP53 hotspot mutations and patient selection e.g., for cell cycle targeting therapies.

The lesion was diagnosed as persistent THOA. This case report discusses the salient features, genetic profile, and prognosis of this uncommon lesion.

Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.

NSCLC cell lines with the mutant R273H allele demonstrated increased susceptibility and apoptosis to proteasome inhibitors. These data suggest that proteasome inhibitors could have therapeutic implications in some subsets of TP53 mutated NSCLC.

These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms.

In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that healthcare disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events which could be exacerbated by therapy-induced cardiotoxicity, need to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

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. >

Our results suggest that differences in the p53 status, even in the hotspot mutation site, affect not only the characteristics of the cells but also the metastatic ability of gastric cancer.

We observed concordance and heterogeneity in the status of actionable mutations between the CSF, peripheral blood, and systemic metastatic tumor tissue. Larger studies are needed to assess the clinical utility of these observations, particularly with the development of several novel targeted agents that are CNS-penetrant.

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.

TP53 aberrant AML cells ( TP53 Aberr ) showed significantly less apoptosis after 48 hr treatment with the cytotoxic drug cytarabine (Arac) (500nM) when compared with TP53 WT AML cells...All the TP53 Aberr AML cells, both mono- and biallelic showed primary resistance to cytotoxic treatment, however under longer exposure to AraC bi-allelic TP53 Aberr AML cells showed higher fitness over mono allelic mutants. Bi-allelic R273H mutant outcompeted biallelic R175H mutant cells indicating a different functional imapct of different TP53 mutations.

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.

The raw and analyzed data are described in this article. They are useful for identifying target genes and consensus binding motifs of the p53 R273H mutant and for further clarifying the molecular mechanism underlying the oncogenic activity of the p53 mutant.

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.

Accordingly, the patient continued Osimertinib combined with Carboplatin/Pemetrexed and with additional palliative irradiation due to a new symptomatic spinal cord compression at L3. Acquired EML4-ALK fusion represents an extremely rare (1%) acquired mechanism of Osimertinib-resistance, which enables further effective and feasible therapy by combining EGFR- and ALK-TKI. Rebiopsies, when possible, are of noteworthy value even in heavily pretreated and fragile patients.

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

Our results have shown that ddPCR can identify both mutations and CNVs in urine and pancreaticobiliary cytology derived samples. Being able to detect these molecular alterations may reduce the number of equivocal results leading to more timely and informed patient management decisions.

With the aim of proposing FADS as a novel target for cancer therapy, the inhibitory effect of Chicago Sky Blue on FADS enzymatic activity was tested on the recombinant 6His-hFADS2 (IC = 1.2 micromolar) and on PANC-1 derived CSCs' lysate (IC = 2-10 micromolar). This molecule was found effective in inhibiting the growth of PANC-1 and even more of its derived CSC line, thus assessing its role as a potential chemotherapeutic drug.

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.

Pathogenic TP53 variants were associated with a shorter overall survival time (p = 0.001).TP53 variants were found to be associated with inferior outcomes in our cohort and can be an independent risk factor for poor prognosis in childhood acute leukemia patients. Identification of low-frequent variants with next-generation sequencing approaches enables better knowledge of the clonal dynamics of ALL.

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.

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.

Combination of talazoparib and temozolomide induced higher DNA double-strand breaks in mtp53 organoids as shown by increased gamma-H2AX expression. The results obtained demonstrated that in mtp53 PDTO synergism is achieved with combined talazoparib-temozolomide treatment supporting the idea that tumors expressing mtp53 may be potential candidates for this combination PARPi treatment.

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.

Whole larvae RNA sequencing and DNA methylation analyses are in progress to reveal mutation-specific mechanisms and pathways, which may reveal novel molecular targets for therapeutic intervention. tp53 R217H and R242H mutants are currently being subjected to treatment with pCAPs (p53 conformation activating peptides) that restore p53 tumor-suppressive hallmarks and/or re-establish native p53 folding to potentially prevent tumor initiation.Significance: In sum, these zebrafish LFS models hold tremendous potential to unravel the pathogenesis of tumor formation in this cancer predisposition syndrome and facilitate a precision-medicine approach to cancer surveillance and prevention to increase survival and enhance quality of life for this vulnerable population.

These findings predict decreased fertility and risk of malignancies in the future. The spectrum of p53 mutations due to polypropylene exposure in the Pakistani population has not been investigated before. Further studies and meta-analyses are required to elucidate the role of different plasticizers in reproduction and cancer-causing risk factors in a larger population.

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

In this limited study, PRAME is expressed in 100% of PEComas demonstrating its utility as an additional IHC marker of melanocytic expression in this difficult tumor type. While PRAME expression was similar to HMB45 in most cases, it was stronger and more diffuse in two cases (33.3%). Additional testing to determine the expression of PRAME in tumors in the differential diagnosis with PEComas is underway.

Venetoclax, CPX-351)... In a TP53 -mutated AML cohort with complex karyotype, we identified a small group of patients younger than 70 years carrying TP53 MS and lacking MK with distinctly superior 2-yr OS regardless of AML subtype.

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

Our study highlights the importance of GOF-P53 and YAP in NSCLC proliferation and proposes autophagy inhibition as an efficient strategy to attenuate NSCLC tumorigenesis.

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%.

Lastly, especially in presence of human 3KR mutant, a high expression of proteins involved in the antioxidant response is found. However, this response does not avoid the increased lipid peroxidation, confirming that only wild type P53 is able to completely counteract the oxidative stress and relative damages.

The cumulative evidence of the proteasome hyperactivity and increased susceptibility of mutant p53 lung cancer cell lines to proteasome inhibition suggest that proteasome hyperactivity could be a targetable vulnerability in mutant p53 lung cancer. Proteasome inhibition could be used as an indirect targeting strategy to increase susceptibility of mutant p53 NSCLC to other targeted and chemotherapeutic approaches.

These cells also exhibited impaired response to hydroxyurea (HU) replicative stress, decreased sensitivity to the PARP-trapping drug combination temozolomide-talazoparib, and increased phosphorylated 53BP1 foci, suggesting reduced Okazaki fragment processing. Implications: The C-terminal region of mtp53 confers GOF activity that mediates mtp53-PARP1 and PAR interactions assisting DNA replication, thus implicating new biomarkers for PARP inhibitor therapy.

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%.