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BIOMARKER:

TP53 Y220C

i
Other names: TP53, Tumor Protein P53, Cellular Tumor Antigen P53, Phosphoprotein P53, Tumor Protein P53, Antigen NY-CO-13, Transformation-Related Protein 53, Mutant Tumor Protein 53, P53 Tumor Suppressor, Tumor Suppressor P53, Tumor Protein 53, BMFS5, TRP53, BCC7, LFS1
Entrez ID:
3ms
Novel 3-(pyrazol-4-yl)-2-(1H-indole-3-carbonyl)acrylonitrile derivatives induce intrinsic and extrinsic apoptotic death mediated P53 in HCT116 colon carcinoma. (PubMed, Sci Rep)
All mechanisms suggested that compound 7f could act as a professional chemotherapeutic agent. Also, a molecular docking study was achieved on some selected proteins implicated in cancer (Caspase 9, XIAP, P53 mutant Y220C, and MDM2) which showed variable interactions with compound 7f with good Gibbs free energy scores.
Journal
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TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase) • CASP9 (Caspase 9) • XIAP (X-Linked Inhibitor Of Apoptosis)
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TP53 mutation • TP53 Y220C • CASP9 mutation
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5-fluorouracil
4ms
Identification and characterization of immunogenic neoantigens in biliary cancer (BC) and pancreatic cancer (PC). (ASCO-GI 2024)
This is the largest study to investigate the landscape of immunogenic neoantigens in BC and PC. The frequency of high-level binding affinity neoantigens was relatively low and associated with relatively lower TIS scores in MSS tumors, which may contribute to the immunogenic cold TME characterizing these tumor types.
MSi-H Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MSH3 (MutS Homolog 3)
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TP53 mutation • KRAS mutation • MSI-H/dMMR • KRAS G12D • KRAS G12 • TP53 Y220C • TP53 R273C
5ms
Stem-Cell Enriched Cellular Hierarchy of TP53 Mutant Acute Myeloid Leukemia Is Vulnerable to Targeted Protein Degradation of c-MYC (ASH 2023)
GT19715 but did not reduce total mouse BM CD45+ cells, suggesting favorable toxicity profiles of GT19715. In conclusion, TP53mut AML comprised highly enriched LSC populations compared to TP53wt AML and targeting of c-MYC protein is highly effective in TP53mut AML in vitro and in vivo with a therapeutic window between AML LSC and normal hematopoietic cells.
IO biomarker
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NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CRBN (Cereblon) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • MECOM (MDS1 And EVI1 Complex Locus)
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TP53 mutation • NRAS mutation • TP53 wild-type • MYC expression • MECOM rearrangement • TP53 Y220C
5ms
Selective Targeting of TP53-Y220C Mutant AML By PC14586 Results in TP53 Wild-Type Conformation and Synergistical Apoptosis Induction By Concomitant Inhibition of Xpo-1, MDM2, or Bcl-2 (ASH 2023)
Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.
PARP Biomarker • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD34 (CD34 molecule) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
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TP53 mutation • TP53 wild-type • TP53 R175H • TP53 Y220C
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rezatapopt (PC14586)
5ms
TP53 Y220C Mutations in Patients with Myeloid Malignancies (ASH 2023)
A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022)... TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.
Clinical
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TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
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TP53 mutation • DNMT3A mutation • TET2 mutation • TP53 Y220C
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rezatapopt (PC14586)
6ms
Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants. (PubMed, NPJ Breast Cancer)
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.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 R248Q • TP53 Y220C • TP53 R273H • TP53 G245S • TP53 R273C
6ms
Clinical • P1/2 data • Late-breaking abstract • Metastases
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 Y220C
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rezatapopt (PC14586)
7ms
Flavonoids as potential reactivators of structural mutation p53Y220C by computational and cell-based studies. (PubMed, J Biomol Struct Dyn)
In the cell-based cytotoxicity studies using p53Y220C harbouring BxPC-3 cell lines, the compounds MPA and MPB showed 75% cell death at 100 µM concentration. We proposed that the flavonoids MPA and MPB have the therapeutic potential to restore p53Y220C and could be used as a combinatorial therapy to reduce the dosage burden.Communicated by Ramaswamy H. Sarma.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 Y220C
7ms
CRISPR single base-editing: in silico predictions to variant clonal cell lines. (PubMed, Hum Mol Genet)
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.
Preclinical • Journal
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TP53 mutation • TP53 wild-type • TP53 R248Q • TP53 Y220C
8ms
2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran, a Benzofuran Derivative, Suppresses Metastasis Effects in P53-Mutant Hepatocellular Carcinoma Cells. (PubMed, Biomedicines)
BMBF had anti-metastatic effects in PLC/PRF/5-an HCC cell line with R249S, a mutated p53 gene. Our findings indicate that BMBF has anti-metastatic effects in downregulating p53 and mediating the suppression of integrin α7, EMT, and MMP-9 in HCC cells with a mutated p53 gene.
Journal
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TP53 (Tumor protein P53) • CDH1 (Cadherin 1) • VIM (Vimentin) • MMP9 (Matrix metallopeptidase 9) • SNAI2 (Snail Family Transcriptional Repressor 2)
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TP53 mutation • CDH1 expression • TP53 Y220C • VIM expression
9ms
New P2 trial • Metastases
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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TP53 mutation • ALK positive • TP53 R175H • TP53 R248Q • TP53 Y220C • TP53 R273H • TP53 R273C
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AiTan (rivoceranib) • AiRuiYi (fluzoparib) • adebrelimab (SHR-1316)
10ms
In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries. (PubMed, Gynecol Oncol Rep)
Identification of 'POLE-like' groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC.
Journal
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TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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TP53 mutation • TP53 wild-type • POLE mutation • TP53 Y220C • POLE EDM
10ms
De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic RECQL4 variants. (PubMed, Blood Sci)
The co-occurring U2AF1 p.S34F and TP53 p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum of RECQL4 and provides underlying molecular mechanism for the development of MDS in RTS patients.
Journal
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TP53 (Tumor protein P53) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • RECQL4( RecQ Like Helicase 4)
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TP53 mutation • U2AF1 mutation • TP53 Y220C • RECQL4 mutation • U2AF1 S34F
12ms
The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE) (clinicaltrials.gov)
P1/2, N=181, Recruiting, PMV Pharmaceuticals, Inc | Trial completion date: Dec 2025 --> Jul 2026 | Trial primary completion date: Nov 2024 --> Mar 2026
Trial completion date • Trial primary completion date • Metastases
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 Y220C
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Keytruda (pembrolizumab) • rezatapopt (PC14586)
1year
OncoKB, MSK’s precision oncology knowledge base (AACR 2023)
For example, OncoKB included 2 new tumor-agnostic FDA drug approvals, dabrafenib + trametinib and selpercatinib for BRAF V600E and RET fusion-positive solid tumors respectively (Level 1), capturing 5 tumor-agnostic FDA drug approvals to date. OncoKB promoted ERBB2 oncogenic mutations and FGFR1 fusions to Level 1 following their inclusion as patient eligibility criteria in FDA drug labels for trastuzumab deruxtecan (NSCLC) and pemigatinib (myeloid/lymphoid neoplasms) respectively...Lastly, previously considered undruggable targets, TP53 Y220C and KRAS G12D, were included in OncoKB based on compelling evidence demonstrating response to allele-targeting drugs, PC14586 and RMC-6263, respectively...Current OncoKB efforts are focused on prioritized high-volume cancer gene curation for annotation of whole exome/genome data, annotation of germline alterations and development of a clinical trials matching system. *FDA recognition of OncoKB is partial and limited to the information clearly marked on www.oncokb.org.
BRCA Biomarker • PARP Biomarker
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • RET (Ret Proto-Oncogene) • FGFR1 (Fibroblast growth factor receptor 1) • BRCA (Breast cancer early onset)
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BRAF V600E • BRAF V600 • HER-2 mutation • KRAS G12D • RET fusion • FGFR1 mutation • KRAS G12 • FGFR1 fusion • BRCA mutation • TP53 Y220C • RET positive
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Mekinist (trametinib) • Tafinlar (dabrafenib) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Retevmo (selpercatinib) • Pemazyre (pemigatinib) • rezatapopt (PC14586)
1year
APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines (AACR 2023)
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.
Preclinical
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TP53 (Tumor protein P53) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
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TP53 mutation • TP53 wild-type • TP53 R248Q • TP53 Y220C • TP53 R273H • TP53 R273C
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eprenetapopt (APR-246) • Nutlin-3
1year
Altered HLA-A2-restricted TP53 epitope induces specific CTL cytotoxicity against hepatocellular carcinoma. (PubMed, Eur J Immunol)
More importantly, in vivo assays demonstrated greater inhibition of HCC cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and NOD/SCID mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • HLA-A*02:01 • TP53 expression • TP53 Y220C
1year
Concordance of Actionable Mutations in Liquid Biopsies and Matched Tumor Tissue of Brazilian Non-small Cell Lung Cancer (NSCLC) (LALCA 2023)
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.
Liquid biopsy • Biopsy • Discordant
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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KRAS G12C • EGFR T790M • KRAS G12D • KRAS G12V • KRAS G13D • KRAS G12 • PIK3CA E542K • KRAS G13 • TP53 R175H • KRAS Q61H • ALK R1275Q • BRAF G469A • EGFR E709K • MAP2K1 P124Q • PIK3CA E542 • TP53 R248Q • TP53 Y220C • EGFR E746 • MAP2K1 E203K • MAP2K1 P124 • TP53 R273C
|
Oncomine™ Lung cfDNA Assay
over1year
A Descriptive Analysis of TP53 Y220C Mutations in Patients with Hematologic Malignancies (ASH 2022)
Recently, a Phase 1 clinical trial studying the novel Y220C-targeted small molecule PC14586, has shown preliminary safety and efficacy in patients with heavily treated solid tumors...Conclusion s : TP53 Y220C mutation is present in hematologic diseases, primarily in myeloid neoplasms (MDS and AML) and with higher frequency in therapy-related disease. Targeted therapies for this specific TP53 mutation would be of interest in this difficult to treat patient population.
Clinical
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TP53 (Tumor protein P53)
|
TP53 mutation • TP53 Y220C
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rezatapopt (PC14586)
over1year
Evaluating Stem Cells to Predict Post-Transplant Relapse in the Myelodysplastic Syndromes (ASH 2022)
Validation of this assay in larger cohorts promises to yield a tool to identify patients who may benefit from early post-transplant interventions to forestall relapse. We also demonstrate how this assay can reveal novel insights into human disease HSC biology.
IO biomarker
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TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • DDX41 (DEAD-Box Helicase 41)
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TP53 mutation • ASXL1 mutation • DDX41 mutation • DNMT3A R882H • IDH2 R140Q • TP53 Y220C • DNMT3A R882
over1year
Individualized therapy based on the combination of mini-PDX and NGS for a patient with metastatic AFP-producing and HER-2 amplified gastric cancer. (PubMed, Oncol Lett)
The mini-PDX model confirmed that the patient's tumor was sensitive to a combination regimen of irinotecan and tegafur-gimeracil-oteracil (S-1)...After six courses of treatment with a regimen comprising 300 mg irinotecan on day 1 + 40 mg S-1 twice daily on days 2-15 + 350 mg trastuzumab once-every 3 weeks, the patient continued with S-1 treatment for 4 courses and trastuzumab for 1 year...Thus, the mini-PDX model combined with the NGS rapidly assessed drug sensitivity in a patient with GC and revealed key genetic mutations. However, the proposed technique requires further research to confirm its potential in the individualized treatment of patients with refractory malignancies.
Journal • Next-generation sequencing
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • MSH6 (MutS homolog 6) • UGT1A1 (UDP glucuronosyltransferase family 1 member A1)
|
HER-2 amplification • UGT1A1*28 • TP53 Y220C • UGT1A1*1*1 • UGT1A1 mutation
|
Herceptin (trastuzumab) • irinotecan • Teysuno (gimeracil/oteracil/tegafur)
over1year
Mechanism of apoptosis activation by curcumin rescued mutant p53Y220C in human pancreatic cancer. (PubMed, Biochim Biophys Acta Mol Cell Res)
By label-free proteomics analysis, we observed that upon curcumin treatment almost 227 proteins were dysregulated with the majority of them being transcriptional targets of p53. Based on our studies, reflects that apoptosis in pancreatic cancer cells is mediated by curcumin-rescued mutant p53Y220C.
Journal
|
TP53 (Tumor protein P53)
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TP53 mutation • TP53 Y220C
over1year
Targeted Next-Generation Sequencing Analysis of 2 Undifferentiated Carcinomas With Osteoclast-like Giant Cells of the Pancreas (CAP 2022)
MED12 mutations have been recently identified in other tumors. Recurrent detection of MED12 mutations in UC-OGC warrants further evaluation of its roles in this unique tumor.
Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • KDM6A (Lysine Demethylase 6A) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD68 (CD68 Molecule)
|
TP53 mutation • KRAS mutation • KRAS G12V • KRAS G12A • KRAS G12 • TP53 mutation + KRAS mutation • TP53 Y220C • KRAS mutation + TP53 mutation
|
FoundationOne® CDx
over1year
Targeted Next-Generation Sequencing Analysis of 2 Undifferentiated Carcinomas With Osteoclast-like Giant Cells of the Pancreas (CAP 2022)
MED12 mutations have been recently identified in other tumors. Recurrent detection of MED12 mutations in UC-OGC warrants further evaluation of its roles in this unique tumor.
Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • KDM6A (Lysine Demethylase 6A) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD68 (CD68 Molecule)
|
TP53 mutation • KRAS mutation • KRAS G12V • KRAS G12A • KRAS G12 • TP53 mutation + KRAS mutation • TP53 Y220C • KRAS mutation + TP53 mutation
|
FoundationOne® CDx
almost2years
Suppression of the Proliferation of Huh7 Hepatoma Cells Involving the Downregulation of Mutant p53 Protein and Inactivation of the STAT 3 Pathway with Ailanthoidol. (PubMed, Int J Mol Sci)
Consistent with ATD, the administration of S3I201 (STAT 3 inhibitor) reduced the expression of Bcl-2/Bcl-xL, cyclin D1, mutp53, and MVK. These results demonstrated ATD's selectivity against mutp53 hepatoma cells involving the downregulation of mutp53 and inactivation of STAT3.
Journal • PARP Biomarker • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1) • BCL2L1 (BCL2-like 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • CDK2 (Cyclin-dependent kinase 2) • TGFB1 (Transforming Growth Factor Beta 1) • ANXA5 (Annexin A5)
|
TP53 mutation • TP53 wild-type • BCL2 expression • CCND1 expression • TP53 expression • STAT3 expression • BAX expression • TP53 Y220C • CDK2 expression
|
GLG-302
almost2years
First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation. (ASCO 2022)
Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts.
Clinical • P1 data
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TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • TP53 Y220C
|
rezatapopt (PC14586)
2years
Small molecule reactivators of Y220C mutant p53 modulate tumor infiltrating leukocytes and synergize with immune checkpoint inhibitors (AACR 2022)
Small molecules that reactivate Y220C mutant p53 activity to be like wild type have been developed at PMV Pharmaceuticals and the lead compound PC14586 is in Phase I clinical development...Further investigation into the role of Y220C p53 reactivation in immune modulation showed decreased cytokines and chemokines involved in inflammation (i.e. CXCL10, Ccl2) and an increase in a Tumor Inflammation Signature (nanoString) in a dose and time dependent manner. Taken together, these data suggest a role for p53 signaling in encouraging an immunologically hot tumor microenvironment and provide support for testing small molecule reactivators of mutant p53 in combination with immune checkpoint inhibitors.
Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
|
TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • MDM2 (E3 ubiquitin protein ligase) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD4 (CD4 Molecule) • CCL2 (Chemokine (C-C motif) ligand 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
TP53 mutation • TP53 Y220C
|
rezatapopt (PC14586)
2years
Investigation for anticancer activity of the newly synthesized p-Methoxyphenyl maleanilic acid and the diagnostic property of its Tc-analogue. (PubMed, Int J Radiat Biol)
The radiolabeled MPMA showed a good localization in the site of solid tumor (15.1 ± 1.6%ID/g) at 2 h post intravenous administration to the tumor bearing mice. Collectively, the findings confirmed the potential anticancer activity of MPMA and the possible use of Tc-MPMA for cancer diagnosis and monitoring.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 Y220C
over2years
Co-Targeting Intrinsic and Extrinsic Apoptosis to Maximize Cell Death Induction in Venetoclax-Resistant AML Cells (ASH 2021)
We next treated NSG mice harboring PDX cells derived from an AML patient who relapsed on the VEN/decitabine therapy with APG2575 (50 mg/kg, p.o., daily), APG1387 (10 mg/kg, i.v., once/wk), APG115 (50 mg/kg, p.o., daily at wk 1 and 5), or combinations. Only in the triple combination group, cIAP1, cIAP2, and XIAP as well as MDM2 were largely diminished and p21 was marked decreased. In conclusion, our study demonstrates that co-targeting intrinsic and extrinsic apoptosis maximizes cell death induction in AML cells with acquired resistance to VEN or with TP53 deletion/mutations by antagonizing Bcl-2, eliminating cIAPs and XIAP, as well as MDM2 and p21, a finding that needs to be validated clinically.
IO biomarker
|
MDM2 (E3 ubiquitin protein ligase) • BIRC3 (Baculoviral IAP repeat containing 3) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • XIAP (X-Linked Inhibitor Of Apoptosis) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
TP53 mutation • TP53 deletion • TP53 R175H • TP53 R248Q • TP53 Y220C • TP53 R213
|
Venclexta (venetoclax) • decitabine • alrizomadlin (APG-115) • lisaftoclax (APG-2575) • APG-1387
over2years
Combined Inhibition of Bcl-2 and Mcl-1 Circumvents Resistance of TP53 Deficient/Mutant AML to BH3 Mimetics (ASH 2021)
This is due primarily to limited responses to available therapies including the highly promising FDA-approved combination of Bcl-2 inhibition by venetoclax (VEN) with hypomethylating agents (DiNardo CD et al., Blood 2020), which resulted in CR/CRi rates of 70-95% and good tolerability in elderly patients (DiNardo CD et al., Lancet Oncol 2018 and Blood 2019)...The Bax KD cells were resistant to VEN and AMG 176, while the combination of the two agents synergistically induced cell death...Thus, targeting Bcl-2 or Mcl-1 individually is insufficient and inhibition of both proteins is needed to shift cell fate from survival to death and circumvents resistance of TP53 deficient/mutant AML and AML stem/progenitor cells to BH3 mimetics. The concept warrants further clinical evaluation.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • BAX (BCL2-associated X protein)
|
TP53 mutation • TP53 R175H • MCL1 expression • TP53 expression • BAX expression • TP53 R248Q • TP53 Y220C • TP53 R273H • TP53 R213
|
Venclexta (venetoclax) • tapotoclax (AMG 176)
almost3years
Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic imidazolate framework-8. (PubMed, Biomaterials)
ZIF-8 modified with an Z1-RGD peptide, exhibiting enhanced cellular internalization and improved decomposition behavior, preferentially killed mutp53-expressing cancer cells and demonstrated remarkable therapeutic efficacy in a p53 S241F ES-2 ovarian cancer model as well as in a p53 Y220C patient-derived xenograft (PDX) breast cancer model. The ability to induce wide-spectrum mutp53 degradation gives ZIF-8 a clear advantage over other degradation-inducers, and engineered nanomaterials may be promising alternatives to small molecules for the development of mutp53-targeting drugs.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 expression • TP53 Y220C
almost3years
Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells. (PubMed, Int J Mol Sci)
We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 Y220C
3years
[VIRTUAL] PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development (AACR 2021)
PC14586 is well tolerated by pre-clinical species and possesses a favorable development profile. The safety and efficacy of PC14586 is currently being evaluated in a seamless Phase I/II clinical study that is a biomarker driven, solid tumor agnostic trial with patients whose tumor bears the Y220C TP53 mutation (NCT study identifier NCT04585750).
Clinical • Late-breaking abstract
|
TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase) • GDF15 (Growth differentiation factor 15) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
TP53 mutation • BAX expression • TP53 Y220C
|
rezatapopt (PC14586)
over3years
[VIRTUAL] EGFR-L858R NSCLC with Pleiotropic Resistance Mechanisms: T790M, C797S, SCLC-Transformation and KRAS, TP53, and BRAF Mutations. (IASLC-WCLC 2020)
Carboplatin/Etoposide was initiated while continuing Osimertinib...Osimertinib was continued and chemotherapy modified to Carboplatin/Pemetrexed...Osimertinib was continued together with Gefitinib...In our patient, persistent EGFR-L858R mutation in the cfDNA 6 months after Erlotinib-start and 11 months after Osimertinib-start correlated with aggressive disease course. 3. The TKI-resistance mechanisms observed in the terminal phase (KRAS- and BRAF-mutations) represent targets for emerging combination-treatment options that are appearing in the repertoire of targeted therapies for NSCLC and may lead extended control of this complex disease in the future.
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53)
|
TP53 mutation • BRAF V600E • KRAS mutation • EGFR mutation • BRAF mutation • BRAF V600 • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • KRAS G12V • EGFR C797S • KRAS G12 • TP53 Y220C
|
Oncomine™ Lung cfDNA Assay
|
Tagrisso (osimertinib) • erlotinib • carboplatin • gefitinib • pemetrexed • etoposide IV
over3years
Curcumin rescue p53Y220C in BxPC-3 pancreatic adenocarcinomas cell line: Evidence-based on computational, biophysical, and in vivo studies. (PubMed, Biochim Biophys Acta Gen Subj)
The study indicated that the natural compound curcumin could rescue mutant p53Y220C in BxPC-3 pancreatic adenocarcinomas cell line to function like wild-type and activate apoptotic pathways.
Preclinical • Journal
|
CHEK1 (Checkpoint kinase 1)
|
TP53 mutation • TP53 Y220C