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Principal Investigator: Rachel E. Lew
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $37,594
Funding agency: National Cancer Institute
TITLE
Biochemical properties and implications of NRAS mutant-specific BRAF interactions in melanoma
ABSTRACT
Extracellular growth factors promote cellular proliferation, motility, and survival through a complex network of
signal transduction pathways. Thus, mutations in these pathways can cause inappropriate cellular proliferation
and lead to diseases, such as cancer. RAS, an intracellular hub for multiple signaling pathways, is mutated in
20-30% of all human cancers. While the three RAS isoforms (H-, K-, and N-RAS) share a high degree of
similarity, each RAS-driven cancer type is enriched for mutations in a specific RAS isoform, codon (12, 13, or
61), and amino acid. We do not fully understand the mechanism driving this observed selectivity, although each
RAS mutant has distinct biochemical and functional properties. Elucidating the mechanisms underlying these
mutational preferences could help identify the features of oncogenic RAS required to initiate cancer in different
tissue types.
To address this knowledge gap, we have focused on the selection of specific NRAS mutants in melanoma. Our
work has shown that common melanoma-associated NRAS mutants (Q61R, K) promote MAPK signaling through
increased activation of BRAF homo- and hetero-dimers. New molecular dynamics simulations suggest that
conformational properties, specific to the NRAS mutants that drive melanoma, facilitate BRAF binding. Here, I
will test the hypothesis that structural differences between NRAS mutants determine their ability to
outcompete autoinhibitory BRAF interactions, drive enhanced MAPK>ERK activation, and alter the
potency of RAF inhibitors. To test my hypothesis, I will use a variety of in vitro biosensors, cell-based signaling
assays, and mouse models to define the mutant-specific features of NRAS that facilitate BRAF interactions (Aim
1) and how the structural determinants of different NRAS mutant-BRAF interactions influence BRAF inhibitor
sensitivity (Aim 2). Successful completion of these studies will enhance my knowledge of structural biology,
therapeutic development, and mouse models of cancer. I will also identify mutant-specific NRAS-BRAF
interfaces to guide the design of novel therapeutic approaches for NRAS-mutant cancers and provide information
relevant to the clinical implementation of next-generation RAF inhibitors.
Terms: <Address><Affinity><Amino Acids><Assay><Automobile Driving><B-raf-1><BRAF><BRAF gene><Binding><Bioassay><Biochemical><Biological Assay><Bioluminescence><Biosensor><Body Tissues><C-K-RAS><Cancer Model><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Proliferation><Cellular Transformation><Clinical Trials><Codon><Codon Nucleotides><Colorectal Cancer><Complement><Complement Proteins><Complex><Cysteine-Rich Domain><Data><Dimerization><Disease><Disorder><Drugs><Energy Transfer><Exhibits><Extracellular Signal-Regulated Kinase Gene><Genetic Alteration><Genetic Change><Genetic defect><Growth Agents><Growth Factor><Growth Substances><H-ras><H-ras Gene><H-ras Oncogene><HRAS><HRAS gene><HRAS1><Harvey Rat Sarcoma Viral Oncogene Homolog><Homo><Human><Immunoblotting><In Vitro><Individual><Intracellular Communication and Signaling><Isoforms><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Knowledge><MAP Kinase Gene><MAPK><Malignant Melanoma><Malignant Neoplasms><Malignant Thyroid Gland Neoplasm><Malignant Tumor><Malignant Tumor of the Thyroid><Malignant Tumor of the Thyroid Gland><Malignant neoplasm of thyroid><Measures><Medication><Melanoma><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Interaction><Molecular Stereochemistry><Motility><Murine><Mus><Mutate><Mutation><N-RAS><NRAS gene><Neuroblastoma RAS viral oncogene><Oncogene K-Ras><Oncogenic><Pathway interactions><Pharmaceutical Preparations><Property><Protein Dimerization><Protein Isoforms><Proteins Growth Factors><RAFB1><RAS driven cancer><RAS driven malignancy><RAS genes><RASH1><RASK2><Ras/Raf><Reporter><Research><Signal Pathway><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Testing><Thyroid Cancer><Tipifarnib><Tissues><Variant><Variation><Western Blotting><Western Immunoblotting><Work><aminoacid><biological sensor><biological signal transduction><cancer initiation><cancer type><clinical implementation><clinical relevance><clinically relevant><complementation><conformation><conformational><conformational state><conformationally><conformations><conformer><design><designing><driving><drug discovery><drug sensitivity><drug/agent><experience><experiment><experimental research><experimental study><experiments><extracellular><gene locus><genetic locus><genome mutation><genomic location><genomic locus><in vivo><inhibitor><leukemia><malignancy><melanocyte><metaplastic cell transformation><molecular dynamics><mouse model><murine model><mutant><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><next generation><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathway><preference><protein blotting><structural biology><structural determinants><structural factors><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic target><tumor><v-Ha-RAS Harvey Rat Sarcoma Viral Oncogene Homolog><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><v-raf Murine Sarcoma Viral Oncogene Homolog B1>