The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.

10 months ago

Preclinical • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • BRAF mutation • NRAS mutation • KIT exon 11 mutation • NRAS Q61 • KRAS Q61H • KRAS exon 2 mutation • NRAS G13 • NRAS G13R • BRAF exon 11 mutation • BRAF exon 15 mutation

LY3009120

1year

Clonal Medicine Targeting DNA Damage Response Eradicates AML (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 AML 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.

1 year ago

PARP Biomarker

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • RAD51 (RAD51 Homolog A) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • RAD52 (RAD52 Homolog DNA Repair Protein)

FLT3-ITD mutation • FLT3 mutation • DNMT3A mutation • FLT3 D835Y • FLT3 D835 • NRAS G13 • NRAS G13R

over1year

Small nucleotide, copy number and structural variants cooperate to hijack driver genes in extramedullary progression of myeloma (IMW 2023)

The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.

over 1 year ago

Tumor mutational burden • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3)

TP53 mutation • BRAF V600E • KRAS mutation • TMB-H • NRAS mutation • BRAF V600 • RAS mutation • NRAS Q61 • KRAS G13 • NRAS G13 • KRAS Q61 • BRAF G469A • NRAS G13R • KRAS A146V • NRAS A146 • Chr del(1p)

almost2years

Describing the molecular landscape of extramedullary multiple myeloma using whole genome sequencing: Insights into pathology and therapeutic targets (AACR 2023)

MAPK DM were frequent in EMD, and detectable in ctDNA, suggesting roles for both MAPK-targeted therapies and for ctDNA as a biomarker in these patients. A high TMB was identified in patients lacking a MAPK driver mutation; immunotherapy should be considered in this subgroup.

almost 2 years ago

Tumor mutational burden • IO biomarker

TP53 mutation • BRAF V600E • KRAS mutation • TMB-H • NRAS mutation • BRAF V600 • NRAS Q61 • KRAS G13 • NRAS G13 • KRAS Q61 • BRAF G469A • NRAS G13R • KRAS A146V • NRAS A146 • Chr del(1p)

almost2years

Acute Myeloid Leukemia with CEBPA Mutation: Next-Generation Sequencing-Based Computational Approach For Enhancing the Diagnosis of Patients with Potential Germline CEBPA Mutated Predisposition (USCAP 2023)

Recognizing and referring patients with possible germline mutations for appropriate genetic evaluation and testing provides insight into best patient care strategies along with education and testing opportunities for family members. Leukemia based NGS panels may aid as screening tools for detecting potential pathogenic germline variants.

almost 2 years ago

Clinical • Next-generation sequencing

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • KMT2C (Lysine Methyltransferase 2C) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • CD36 (thrombospondin receptor) • MSH3 (MutS Homolog 3) • GATA2 (GATA Binding Protein 2) • PHF6 (PHD Finger Protein 6) • BCORL1 (BCL6 Corepressor Like 1)

NRAS Q61 • CEBPA mutation • NRAS G13 • NRAS Q61L • DNMT3A R882H • IDH1 R132 • NRAS G13D • NRAS G13R • IDH2 R140Q • DNMT3A R882 • NPM1 W288

FoundationOne® Heme CDx

2years

Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa. (PubMed, BMC Cancer)

KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

2 years ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • RAS mutation • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS G12S • KRAS exon 2 mutation • NRAS G12D • NRAS G13 • NRAS Q61L • KRAS A59T • KRAS A146T • NRAS A146T • NRAS G13R • KRAS A146V • KRAS G13C • KRAS exon 3 mutation • KRAS exon 4 mutation • NRAS A146 • NRAS A59 • KRAS Q61L • NRAS G12S • KRAS A146P

over2years

Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation. (PubMed, Nat Commun)

Molecular dynamics simulations, combined with cell-based protein-protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.

over 2 years ago

Journal

BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase)

BRAF mutation • NRAS mutation • NRAS Q61K • NRAS Q61 • NRAS Q61R • NRAS G12D • NRAS G12 • NRAS G13 • NRAS Q61L • NRAS G13D • NRAS G13R

over2years

Liquid biopsy (LB)-based comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) for the evaluation of patients with myeloid neoplasms. (ASCO 2022)

LB identified clinically relevant genomic alterations in myeloid neoplasia, offering a powerful tool that may be used pre- or post-treatment when CGP of the buffy coat, marrow, or tissue is infeasible. Given its low limit of detection, LB can also identify low-level emerging or persistent subclones, which may facilitate monitoring and minimal residual disease testing.

over 2 years ago

Clinical • Liquid biopsy • Circulating tumor DNA

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CHEK2 (Checkpoint kinase 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CALR (Calreticulin)

NRAS mutation • KRAS G12A • KRAS G12 • KRAS G13 • U2AF1 mutation • NRAS G12 • NRAS G13 • JAK2 V617F • NRAS G13R

FoundationOne® Liquid CDx

almost3years

PTEN loss-of-function mutations prevalent in HRAS-mutant cancers results in resistance to targeted therapy (AACR 2022)

‘RASless’ (KRASlox/HRASKO/NRASKO) mouse embryonic fibroblasts (MEFs) were obtained that in the presence of 600nM tamoxifen (4OHT) resulted in a KRAS knock-out...Combined treatment of HRASG13R/PTEN MEFs with the PIK3CB-specific inhibitor AZD8186 and tipifarnib sensitized cells in non-4OHT (IC50- 100nM:100nM Tipifarnib:AZD8186) and 4OHT (IC50- 100nM:10nM Tipifarnib:AZD8186) conditions... Co-altered mutations of MAPK, PI3K or RTK effectors are found more commonly in HRAS than in KRAS or NRAS-mutant cancers. Co-alteration of PTEN preferentially associated with HRAS-mutations in NSCLC. Deletion of PTEN resulted in resistance to FTI targeted therapy in vitro.

almost 3 years ago

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • NF1 (Neurofibromin 1) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta)

NRAS mutation • PTEN deletion • KRAS wild-type • NF1 mutation • HRAS mutation • HRAS G13R • NRAS G13 • NRAS G13R • HRAS G13R

MSK-IMPACT

tamoxifen • Zarnestra (tipifarnib) • AZD8186

3years

Diverse alterations associated with resistance to KRAS(G12C) inhibition. (PubMed, Nature)

Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib...A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

3 years ago

Journal

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR2 (Fibroblast growth factor receptor 2)

KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12V • NRAS Q61K • NRAS Q61 • KRAS G13 • NRAS G12 • NRAS G13 • NRAS G13D • NRAS G13R • KRAS Q61K • NRAS G12V

Lumakras (sotorasib)

almost5years

[VIRTUAL] A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma. (ASCO 2020)

Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Research Funding: Shanghai KeChow Pharma

almost 5 years ago

Clinical • P1/2 data

NRAS (Neuroblastoma RAS viral oncogene homolog)

NRAS mutation • NRAS Q61K • NRAS Q61 • NRAS Q61R • NRAS G12D • NRAS Q61L • NRAS G13R • NRAS G12S

tunlametinib (HL-085)