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BIOMARKER:

NRAS G12

i
Other names: NRAS1, HRAS1, N-Ras Protein Part 4, Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog, NRAS, Neuroblastoma RAS Viral Oncogene Homolog, NRAS Proto-Oncogene, GTPase
Entrez ID:
Related biomarkers:
15d
A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma. (PubMed, Eur J Cancer)
Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.
Clinical • P2 data • Journal • IO biomarker • Metastases
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NRAS (Neuroblastoma RAS viral oncogene homolog)
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NRAS mutation • NRAS Q61 • NRAS G12 • NRAS G13
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tunlametinib (HL-085)
23d
5G2 mutant mice model loss of a commonly deleted segment of chromosome 7q22 in myeloid malignancies. (PubMed, Leukemia)
Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase) • CUX1 (cut like homeobox 1)
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KRAS G12D • KRAS G12 • NRAS G12 • Chr del(7q) • KRAS deletion
30d
Assessment of RAS-RAF-MAPK Pathway Mutation Status in Healthy Skin, Benign Nevi, and Cutaneous Melanomas: Pilot Study Using Droplet Digital PCR. (PubMed, Int J Mol Sci)
Here, we demonstrate that the "young" ddPCR technology is as effective as a CE-IVD marked real-time PCR method for detecting BRAF V600 hotspot mutations in tumor biopsies and recommend it for extended use in clinical settings. Moreover, ddPCR was able to detect low-frequency hotspot mutations, such as NRAS G12/G13, in our tissue specimens, which makes it a promising tool for investigating the mutational landscape of sun-damaged skin, benign nevi, and melanomas in more extensive clinical studies.
Journal • Tumor mutational burden
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BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
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BRAF mutation • NRAS mutation • BRAF V600 • RAS mutation • NRAS G12 • NRAS G13 • NRAS mutation + BRAF mutation
1m
Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer (clinicaltrials.gov)
P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025
Trial completion date • Combination therapy • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • EGF (Epidermal growth factor)
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KRAS mutation • NRAS mutation • BRAF V600 • BRAF wild-type • RAS wild-type • HRAS mutation • KRAS G12 • NRAS Q61 • KRAS G13 • NRAS G12 • NRAS G13 • KRAS Q61 • HRAS Q61
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Mekinist (trametinib)
2ms
GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation. (PubMed, Cell Commun Signal)
Remarkably, depleting GOLGA7 effectively inhibits cell proliferation in multiple NRAS-mutant cancer cell lines and attenuates NRASG12D-induced oncogenic transformation in vivo. These findings elucidate a specific intracellular trafficking route for NRAS under GOLGA7 regulation, highlighting GOLGA7 as a promising therapeutic target for NRAS-driven cancers.
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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NRAS mutation • KRAS G12D • NRAS G12
2ms
Real-world clinical utility of next-generation sequencing ctDNA for patients with advanced lung squamous cell carcinoma (ELCC 2024)
Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.
Real-world evidence • Clinical • Next-generation sequencing • Circulating tumor DNA • Real-world • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • FGFR1 (Fibroblast growth factor receptor 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A)
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TP53 mutation • BRAF V600E • BRAF V600 • EGFR exon 19 deletion • KRAS G12D • EGFR amplification • KRAS G12V • FGFR1 amplification • ALK fusion • KRAS G12R • KRAS G12A • KRAS G12 • KRAS G13 • KRAS amplification • FGFR1 fusion • NRAS G12 • NRAS G13 • KRAS G13C • EGFR fusion • KRAS G61 • KRAS deletion
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InVisionFirst®-Lung
2ms
Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis. (PubMed, Acta Neuropathol Commun)
NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.
Journal
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NRAS (Neuroblastoma RAS viral oncogene homolog) • GNAQ (G Protein Subunit Alpha Q)
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NRAS mutation • GNAQ mutation • NRAS G12 • GNAQ R183Q • NRAS G12V
2ms
Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers. (PubMed, Cancer Discov)
KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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KRAS mutation • NRAS mutation • NRAS G12 • HRAS G12C • NRAS G12C
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Vectibix (panitumumab) • Lumakras (sotorasib) • Krazati (adagrasib)
2ms
Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model. (PubMed, Front Immunol)
Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants. Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways.
Preclinical • Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IFNG (Interferon, gamma) • CCL2 (Chemokine (C-C motif) ligand 2) • TAP1 (Transporter 1) • PSMB8 (Proteasome 20S Subunit Beta 8)
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KRAS mutation • KRAS G12C • RAS mutation • KRAS G12 • NRAS Q61 • NRAS G12 • NRAS Q61L • KRAS Q61L
2ms
Evolutionary dynamics of tipifarnib in HRAS mutated head and neck squamous cell carcinoma. (PubMed, Oral Oncol)
Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.
Journal
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HRAS (Harvey rat sarcoma viral oncogene homolog) • AXL (AXL Receptor Tyrosine Kinase) • YAP1 (Yes associated protein 1)
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HRAS mutation • NRAS G12 • HRAS G12S
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Piqray (alpelisib) • Zarnestra (tipifarnib)
3ms
IN10018 Monotherapy and Combination Therapy for Metastatic Melanoma (clinicaltrials.gov)
P1, N=120, Recruiting, InxMed (Shanghai) Co., Ltd. | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
Trial completion date • Trial primary completion date • Combination therapy • Metastases
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NRAS (Neuroblastoma RAS viral oncogene homolog)
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NRAS mutation • NRAS Q61 • NRAS G12 • NRAS G13
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Tecentriq (atezolizumab) • Cotellic (cobimetinib) • ifebemtinib (IN10018)
3ms
Transcriptome analysis of primary adult B-cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis. (PubMed, Eur J Haematol)
We demonstrate that RNA-seq is an effective tool for precision medicine in B-ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CRLF2 (Cytokine Receptor Like Factor 2) • PDE4DIP (Phosphodiesterase 4D Interacting Protein) • PDE4D (Phosphodiesterase 4D) • DUX4 (Double Homeobox 4)
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KRAS mutation • KRAS G12D • KRAS G13D • KRAS G12 • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • NRAS G13D
3ms
Enrollment change • Trial suspension • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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KRAS mutation • NRAS mutation • KRAS G12V • HRAS mutation • KRAS G12 • NRAS G12 • HLA-A*11 • NRAS G12V
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cyclophosphamide • fludarabine IV • Proleukin (aldesleukin)
3ms
Trial completion date
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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KRAS mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS G12D • NRAS G12
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ELI-002 7P
4ms
Association of KRAS G12C status with age at onset of metastatic colorectal cancer in the Brazilian population: A multicenter analysis of a molecular profile database (RAS, BRAF and MSI status). (ASCO-GI 2024)
In our Brazilian cohort of mCRC patients, frequencies of RAS and BRAF mutations were similar to worldwide data. However, we found lower than expected frequency of MSI-high tumors. KRAS G12C mutation was associated with early-onset mCRC, an emergent population in which KRAS G12C inhibitors might be particulary useful.
Clinical • MSi-H Biomarker • Metastases
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability)
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BRAF V600E • KRAS mutation • MSI-H/dMMR • KRAS G12C • NRAS mutation • KRAS G12D • KRAS G12V • KRAS wild-type • RAS mutation • RAS wild-type • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS G12D • NRAS G12 • KRAS Q61K
4ms
Ubiquitin-specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma. (PubMed, MedComm (2020))
Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti-mTOR-based therapy after LT.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • USP22 (Ubiquitin Specific Peptidase 22) • FKBP5 (FKBP Prolyl Isomerase 5)
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NRAS G12 • USP22 overexpression
4ms
Calr+ Myelofibrosis/BCR-ABL Chronic Myeloid Leukemia Overlap Syndrome Treated with Asciminib (ASH 2023)
Treatment was ruxolitinib and hydroxyurea...He started dasatinib and decitabine, which resulted in a drop from 28...However, hyperuricemia and renal failure led to a change in regimen and the patient was started on asciminib and ropeginterferon alfa-2b-njft in January 2022...He received cladribine and cytarabine, but was found to have leukemic infiltration of the spinal cord five months later...However, he always maintained a high CALR burden. This patient's mutational profile and disease course argue for the importance of early testing for CALR and BCR-ABL in addition to JAK2 and MPL in the setting of an MPN and for further research into the underlying causes of these overlap conditions.
Tumor mutational burden
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TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • CALR (Calreticulin)
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ASXL1 mutation • NRAS G12 • CALR mutation • NRAS G12V
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dasatinib • cytarabine • Jakafi (ruxolitinib) • decitabine • Scemblix (asciminib) • cladribine • hydroxyurea • Besremi (ropeginterferon alfa-2b)
4ms
RTK-RAS Signaling Pathway Was Enriched in Rare Acute Myeloid Leukemia Patients with t(16; 21)(p11; q22)/ FUS: : ERG (ASH 2023)
PTPN11 and NRAS were the most frequent mutations and RTK-RAS signaling pathway was the most involved pathway in rare AML patients with t(16; 21)(p11; q22)/ FUS: : ERG. The addition of signaling pathway inhibitors followed by HSCT might be an effective strategy to overcome the dismal outcome of this subtype. Larger cohort studies are warranted to investigate the molecular characteristics further as well as evaluate the clinical activity of the SHP2 (PTPN11) inhibitors in FUS: : ERG AML patients.
Clinical
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ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • BCOR (BCL6 Corepressor) • CD123 (Interleukin 3 Receptor Subunit Alpha) • NCAM1 (Neural cell adhesion molecule 1) • FUS (FUS RNA Binding Protein) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • SH2B3 (SH2B Adaptor Protein 3)
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KRAS mutation • NRAS mutation • DNMT3A mutation • RUNX1 mutation • RAS mutation • ASXL1 mutation • PTPN11 mutation • NRAS Q61 • BCOR mutation • NRAS G12
4ms
Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma. (PubMed, J Hepatol)
These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR2 (Fibroblast growth factor receptor 2) • BICC1 (BicC Family RNA Binding Protein 1)
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BRAF V600E • KRAS mutation • BRAF V600 • KRAS G12D • FGFR2 mutation • FGFR2 fusion • FGFR fusion • KRAS G12 • NRAS Q61 • FGFR2-BICC1 fusion • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • KRAS Q61 • NRAS G13D • NRAS G12C
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Lytgobi (futibatinib)
5ms
Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis. (PubMed, BMC Cancer)
Contrary to prior assumptions, the G12V NRAS mutant form is sufficient to elicit hepatocarcinogenesis in the mouse. Furthermore, the upregulation of the MAPK cascade was paralleled by the overexpression of DUSP4, DUSP6, and CD133 in vivo and in vitro. Therefore, DUSP4 and DUSP6 might fine-tune the excessive MAPK activation, a mechanism that can potentially be harnessed therapeutically.
Journal
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NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6) • DUSP4 (Dual Specificity Phosphatase 4)
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NRAS mutation • NRAS G12 • CD133 expression • CD133 overexpression • NRAS G12V
5ms
Mediator Kinase/CDK8 Inhibition As a Strategy to Improve FLT3 Inhibitor Activity in Acute Myeloid Leukemia (ASH 2023)
RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IRF8 (Interferon Regulatory Factor 8) • SPI1 (Spi-1 Proto-Oncogene)
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NRAS mutation • FLT3-ITD mutation • FLT3 mutation • RAS mutation • NRAS G12 • Inflammatory gene signature • IRF8 expression • NRAS G12C
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Venclexta (venetoclax) • Xospata (gilteritinib) • RVU120
5ms
In Vivo Modeling of T-Cell Acute Lymphoblastic Leukemia Reveals Synergistic Oncogenic Pathways and Bcl11b Haploinsufficiency As a Potential Therapeutic Vulnerability (ASH 2023)
Using our resource, we identified Bcl11b as a strong and selective context-specific dependency in T-ALL. Although Bcl11b is a transcription factor, our results could serve as an starting point for novel therapies that interfere with Bcl11b function, such as molecular glue degraders or protein interaction inhibitors.
Preclinical
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PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • CD8 (cluster of differentiation 8) • ETV6 (ETS Variant Transcription Factor 6) • IL2RA (Interleukin 2 receptor, alpha) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • PHF6 (PHD Finger Protein 6) • LMO2 (LIM Domain Only 2) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • TLX1 (T Cell Leukemia Homeobox 1)
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PTEN mutation • CDKN2A deletion • NRAS G12 • NOTCH1 deletion • CD4 positive • NOTCH1 overexpression
5ms
Deciphering the Role of RAS Pathway Mutations in the Biology of Human Acute Myeloid Leukemia Using In Vivo Models (ASH 2023)
Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.
Preclinical
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTCH1 (Patched 1) • CD34 (CD34 molecule)
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KRAS mutation • NRAS mutation • KRAS G12D • KRAS wild-type • NF1 mutation • KRAS G13D • RAS mutation • RAS wild-type • KRAS G12 • MLL rearrangement • PTCH1 mutation • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • MLL mutation • NRAS G13D • KMT2A expression • KRAS overexpression • KRAS expression
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cytarabine • Daurismo (glasdegib)
5ms
RASMULTI(ON) Inhibitor RMC-7977 Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 Inhibitors in AML Models (ASH 2023)
RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need.
IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CASP3 (Caspase 3) • CASP7 (Caspase 7)
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KRAS mutation • NRAS mutation • FLT3-ITD mutation • FLT3 mutation • KIT mutation • KRAS G13D • RAS mutation • NRAS Q61K • NRAS Q61 • KIT N822K • NRAS G12 • NRAS G13 • NRAS Q61L • NRAS G13D • NRAS G12C
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Venclexta (venetoclax) • Xospata (gilteritinib) • RMC-6236 • RMC-7977
5ms
N/KRAS-Mutant AML LSCs Originate from Committed Myelomonocytic Progenitors and Drive Clinical Resistance to Venetoclax (ASH 2023)
We reanalyzed data from a cohort of 118 older/unfit newly diagnosed AML patients treated on a prospective clinical trial with VEN and decitabine (DEC) (NCT03404193). It shows for the first time that interaction between an oncogenic driver and the non-genetic developmental hematopoietic hierarchy imposes a specific LSC cell-of-origin restriction and in turn shapes the hierarchical structure of the resulting AML and critically determines therapeutic outcomes in patients. Importantly, our results have direct implications for clinical practice, as they support that RAS MT LSCs drive clinical resistance to VEN and that treatment with VEN in patients with RAS mutations can accelerate disease progression by selection of RAS MT LSCs (Figure).
Clinical • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CD34 (CD34 molecule) • CD14 (CD14 Molecule) • CD68 (CD68 Molecule) • ITGAM (Integrin, alpha M)
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KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • RAS wild-type • KRAS G12 • NRAS G12D • NRAS G12
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Venclexta (venetoclax) • decitabine
5ms
Single Cell Correlation Analysis: A Novel Method to Analyze Single Cell RNA Sequencing Data Identifies a Self-Renewing Subpopulation of Human Acute Myeloid Leukemia Stem Cells (ASH 2023)
Using this method, we demonstrate that primary human AML samples express the single-cell profiles of self-renewal that we previously validated experimentally. SCA-based identification of human self-renewing cells will allow us to interrogate novel transcriptional features of these cells in future studies.
Clinical • IO biomarker
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NRAS (Neuroblastoma RAS viral oncogene homolog) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • CD36 (thrombospondin receptor) • CD69 (CD69 Molecule)
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NRAS G12 • NRAS G12V
5ms
Clonal Targeting of DNA Damage Response Pathways Eradicates Myeloproliferative Neoplasms (ASH 2023)
The "clonal attack" by DDR inhibitors shifts the paradigm of genotoxic therapies from those using non-discriminative cytotoxic drugs to those selectively attacking DDR vulnerabilities in MPN clones with minimal harm to normal cells. Since clonal heterogeneity and DNA damage are hallmarks of cancer, the "clonal attack" may be broadly applicable to the quest for cancer cure.
PARP Biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • RAD51 (RAD51 Homolog A) • CD34 (CD34 molecule) • SETBP1 (SET Binding Protein 1) • RAD52 (RAD52 Homolog DNA Repair Protein)
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DNMT3A mutation • NRAS G12D • NRAS G12 • JAK2 V617F • IDH1 R132
5ms
A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice. (PubMed, J Clin Invest)
The proteasome inhibitor bortezomib stabilized NFκB inhibitory protein IκBα reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergizes with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.
Preclinical • Journal
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TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • GATA2 (GATA Binding Protein 2) • NFKBIA (NFKB Inhibitor Alpha 2)
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TP53 mutation • NRAS mutation • NRAS G12 • TP53 R172H
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bortezomib
6ms
NFAT5 deficiency correlates with features of carcinogenesis in anaplastic thyroid carcinoma in-vitro (DGHO 2023)
Of interest, the cytotoxicity of doxorubicin could be improved by co-incubation with the TKI Lenvatinib in NFAT5-deficient NthyOri3-1 cells. Our investigations suggest that NFAT5 expression is worsened in ATC and that NFAT5 deficiency is stronger associated with prognostic negative characteristics in-vitro .
Preclinical
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BRAF (B-raf proto-oncogene) • HRAS (Harvey rat sarcoma viral oncogene homolog) • NFATC1 (Nuclear Factor Of Activated T Cells 1)
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BRAF V600E • BRAF V600 • HRAS mutation • NRAS G12
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Lenvima (lenvatinib) • doxorubicin hydrochloride
6ms
Clear Cell Squamous Cell Carcinoma of the Maxillary Gingiva Associated with PIK3CA and HRAS Mutations: Report of a Case and Literature Review. (PubMed, Head Neck Pathol)
We report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • EWSR1 (EWS RNA Binding Protein 1) • MME (Membrane Metalloendopeptidase) • MLANA (Melan-A) • TP63 (Tumor protein 63) • MAML2 (Mastermind Like Transcriptional Coactivator 2) • RASA1 (RAS P21 Protein Activator 1)
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TP53 mutation • PIK3CA mutation • PTEN mutation • KRAS G12A • HRAS mutation • PIK3CA E542K • NRAS G12 • PIK3CA E542
6ms
AMPLIFY-201: A Study of ELI-002 in Subjects With KRAS Mutated Pancreatic Ductal Adenocarcinoma (PDAC) and Other Solid Tumors (clinicaltrials.gov)
P1, N=25, Active, not recruiting, Elicio Therapeutics | Trial completion date: Jul 2025 --> Mar 2026
Trial completion date • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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KRAS mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS G12D • NRAS G12
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ELI-002 7P
6ms
LENVATINIB IN COMBINATION WITH ONCOPROTEIN TARGETED MAPK INHIBITORS IN DIFFERENTIATED AND DEDIFFERENTIATED THYROID CANCERS (ATA 2023)
Mice with dedifferentiated tumors treated with 4 weeks of either lenvatinib or dabrafenib/trametinib (dab/tram) for Braf/Arid1a or tipifarnib for Hras/p53 demonstrated tumor progression or stability (% change tumor volume: Braf/Arid1a: vehicle +238. Combination MAPK signaling blockade and angiogenesis inhibition leads to profound anti‐tumor responses across the spectrum of thyroid cancers in GEMMs.
Late-breaking abstract • Combination therapy
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BRAF (B-raf proto-oncogene) • HRAS (Harvey rat sarcoma viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • CD31 (Platelet and endothelial cell adhesion molecule 1) • PECAM1 (Platelet And Endothelial Cell Adhesion Molecule 1)
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BRAF V600E • BRAF V600 • NRAS G12 • BRAF V600E + TERT mutation • CD31 expression • HRAS G12V
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Mekinist (trametinib) • Tafinlar (dabrafenib) • Lenvima (lenvatinib) • Zarnestra (tipifarnib)
6ms
Cellular responses after (neratinib plus pemetrexed) exposure in NSCLC cells. (PubMed, Anticancer Drugs)
These findings argue against the development of 'early' resistance mechanisms after neratinib and pemetrexed exposure. Future studies will be required to understand how NSCLC cells become resistant to neratinib and pemetrexed.
Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • MCL1 (Myeloid cell leukemia 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • BCL2L1 (BCL2-like 1) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • ATG5 (Autophagy Related 5) • BECN1 (Beclin 1)
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KRAS G12C • NRAS mutation • EGFR L858R • HER-2 expression • EGFR T790M • EGFR expression • KRAS G12V • KRAS wild-type • RAS mutation • RAS wild-type • NRAS Q61K • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS G12S • KRAS Q61H • MCL1 expression • NRAS G12 • KRAS Q61K • NRAS G12S
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Nerlynx (neratinib) • pemetrexed