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    BIOMARKER:

    HRAS G12C

    i
    Other names: HRAS, HRAS1, Harvey rat sarcoma viral oncogene homolog
    Entrez ID:
    3265
    Related biomarkers:
    Expression
    Mutation
    Others
    23h
    Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer. (PubMed, Pathol Oncol Res)
    Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog) • RHEB (Ras Homolog, MTORC1 Binding)
    |
    KRAS mutation • KRAS G12D • HRAS G12C • KRAS expression
    |
    MRTX1133
    21d
    FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer. (PubMed, J Thorac Oncol)
    Importantly, treatment of mice with FGTI-2734 inhibited sotorasib-induced ERK reactivation in KRAS G12C PDX, and treatment of mice with the combination of FGTI-2734 and sotorasib were also significantly more effective at suppressing in vivo the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts as well as a PDX. Our findings provide a foundation for overcoming sotorasib resistance and potentially improving the treatment outcomes of KRAS G12C lung cancer.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS G12C • KRAS G12 • NRAS wild-type • HRAS G12C
    |
    Lumakras (sotorasib)
    3ms
    Beyond KRAS(G12C): Biochemical and Computational Characterization of Sotorasib and Adagrasib Binding Specificity and the Critical Role of H95 and Y96. (PubMed, ACS Chem Biol)
    Unlike adagrasib, sotorasib is less dependent on H95 for its binding, making it a RAS isoform-agnostic compound, having a similar functionality also with NRAS and HRAS G12C mutants. Our results emphasize the accessibility of SII-P beyond oncogenic G12C and aid in understanding the molecular mechanism behind the clinically observed drug resistance, associated especially with secondary mutations on KRAS H95 and Y96.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS G12C • HRAS mutation • KRAS G12 • NRAS G12 • HRAS G12C
    |
    Lumakras (sotorasib) • Krazati (adagrasib)
    8ms
    Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. (PubMed, Nature)
    Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • NRAS mutation • KRAS wild-type • RAS wild-type • HRAS mutation • NRAS wild-type • HRAS G12C • HRAS wild-type
    |
    RMC-6236 • RMC-7977
    8ms
    Probing RAS Function Using Monobody and NanoBiT Technologies. (PubMed, Methods Mol Biol)
    To do this, we have exploited the use of monobody (Mb) technology to develop specific protein-based inhibitors of selected RAS isoforms and mutants (Spencer-Smith et al., Nat Chem Biol 13:62-68, 2017; Khan et al., Cell Rep 38:110322, 2022; Wallon et al., Proc Natl Acad Sci USA 119:e2204481119, 2022; Khan et al., Small GTPases 13:114-127, 2021; Khan et al., Oncogene 38:2984-2993, 2019). Herein, we describe our combined use of Mbs and NanoLuc Binary Technology (NanoBiT) to analyze RAS protein-protein interactions and to screen for RAS-binding small molecules in live-cell, high-throughput assays.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • RAS mutation • HRAS mutation • HRAS G12C
    9ms
    Farnesyltransferase inhibitors have antitumoral effects in mutant KRAS containing cancer cells in preclinical models (PubMed, Magy Onkol)
    Accordingly, we have tested FTIs (tipifarnib and lonafarnib) in G12C mutant human cancer cell lines in vitro and in vivo. At last, we have also tested FTIs on G12V mutant human cancer cells and again we have detected antitumoral effects. We suggest that FTIs may have clinical relevance outside the HRAS mutant cancers.
    Preclinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • HRAS mutation • HRAS G12C
    |
    Zarnestra (tipifarnib)
    10ms
    RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains. (PubMed, J Cell Biol)
    Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains...Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • KRAS G13D • RAS mutation • HRAS mutation • KRAS G12 • HRAS G12C
    11ms
    Farnesyl-transferase inhibitors show synergistic anticancer effects in combination with novel KRAS-G12C inhibitors. (PubMed, Br J Cancer)
    Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
    Journal • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog) • RHEB (Ras Homolog, MTORC1 Binding)
    |
    KRAS mutation • HRAS G12C
    |
    Lumakras (sotorasib) • Zarnestra (tipifarnib)
    11ms
    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
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • NRAS mutation • NRAS G12 • HRAS G12C • NRAS G12C
    |
    Vectibix (panitumumab) • Lumakras (sotorasib) • Krazati (adagrasib)
    1year
    Palbociclib and Binimetinib in RAS-Mutant Cancers, A ComboMATCH Treatment Trial (clinicaltrials.gov)
    P2, N=199, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting
    Enrollment open
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • RAS (Rat Sarcoma Virus)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • HRAS mutation • KRAS G12 • HRAS G12C
    |
    Ibrance (palbociclib) • Mektovi (binimetinib)
    1year
    Characterizing Intraprimary Tumor Genetic Heterogeneity in Colorectal Carcinoma with Multiple Driver Alterations (AMP 2023)
    These data support that the tumor likely arose from three separate clonal populations, the BRAF V600E population and the KRAS G12G and KRAS G12C populations, each having distinct molecular pathways to tumorigenesis. Future directions include measuring spatial gene expression patterns of the tumor to correlate with the tumor mapping described above and to further characterize the multiple populations of tumor cells harboring different driver alterations and molecular pathways to tumorigenesis.
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • BRAF V600 • KRAS G12D • BRAF V600K • KRAS G12 • KRAS exon 2 mutation • NRAS G12D • HRAS G12C • BRAF V600E + KRAS G12D
    |
    Cologuard®
    over1year
    Small molecular inhibitors for KRAS-mutant cancers. (PubMed, Front Immunol)
    Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.
    Review • Journal • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • RAS mutation • HRAS mutation • KRAS G12 • HRAS G12C
    |
    Lumakras (sotorasib)
    over1year
    Recent advances in the development of inhibitors targeting KRAS-G12C and its related pathways. (PubMed, Eur J Med Chem)
    In 2021, the FDA approved AMG510, the first direct inhibitor targeting the KRAS-G12C mutation, which has shown tumor regression, prolonged survival, and low off-target activity...Therefore, a large number of other highly efficient inhibitors are being developed at different stages. This article provides an overview of the mechanism of action targeting KRAS-G12C in the KRASGTP-KRASGDP cycle pathway, as well as the structure-activity relationship, structure optimization, and biological activity effects of inhibitors that target the upstream and downstream pathways, or combination therapy.
    Review • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • HRAS G12C
    |
    Lumakras (sotorasib)
    over1year
    Palbociclib and Binimetinib in RAS-Mutant Cancers, A ComboMATCH Treatment Trial (clinicaltrials.gov)
    P2, N=199, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2022 --> Sep 2023
    Trial initiation date
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • HRAS mutation • KRAS G12 • HRAS G12C
    |
    Ibrance (palbociclib) • Mektovi (binimetinib)
    over1year
    Whole-exome sequencing of secondary tumors arising from nevus sebaceous revealed additional genomic alterations besides RAS mutations. (PubMed, J Dermatol)
    In conclusion, our study revealed that secondary tumors arising from NS harbor known RAS hotspot mutations and additional genomic alterations, including putative driver mutations and PTCH1 copy-loss. These results could help to define the high-risk group for tumor development in patients with NS and provide evidence for prophylactic resection.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • PTCH1 (Patched 1) • RAS (Rat Sarcoma Virus)
    |
    TP53 mutation • KRAS G12C • KRAS G12D • RAS mutation • HRAS G13R • KRAS G12 • NRAS Q61R • PTCH1 mutation • KRAS G13 • NRAS G12 • HRAS G12C • HRAS Q61R • HRAS G13R • SMO W535L • TP53 R213
    almost2years
    Overcoming KRAS G12C inhibitor resistance with a chaperone-mediated protein degrader (CHAMP) (AACR 2023)
    While KRAS has been undruggable, covalent KRAS G12C inhibitors, sotorasib and adagrasib, that bind preferentially to GDP-bound KRAS and prevent exchange for GTP and interaction with downstream effectors, have been approved for use in NSCLC. Furthermore, in vivo treatment with RNK07421 demonstrated dramatic tumor growth inhibition as compared to adagrasib treatment alone. Together, these observations indicate that the novel mechanisms of action of RNK07421 may provide several advantages over G12C inhibitors and possibly other targeted protein degradation agents to effectively treat KRAS G12C-dependent NSCLC.
    Late-breaking abstract
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    KRAS mutation • RAS mutation • HRAS G12C
    |
    Lumakras (sotorasib) • Krazati (adagrasib) • RNK07421
    2years
    Palbociclib and Binimetinib in RAS-Mutant Cancers, A ComboMATCH Treatment Trial (clinicaltrials.gov)
    P2, N=199, Not yet recruiting, National Cancer Institute (NCI)
    New P2 trial
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • HRAS mutation • KRAS G12 • HRAS G12C
    |
    Ibrance (palbociclib) • Mektovi (binimetinib)
    over2years
    Comprehensive analysis of the association between RAS mutation and immune checkpoint marker expression (ESMO 2022)
    VTCN1 is a co-inhibitory molecule which negatively regulates T-cell immune response and promotes immune escape. The association between genetic mutations in cancer cells and the immune status in the tumor microenvironment may suggest potential treatment with combination targeted therapy plus immunotherapy.
    PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • PD-1 (Programmed cell death 1) • LAG3 (Lymphocyte Activating 3) • RAS (Rat Sarcoma Virus) • VTCN1 (V-Set Domain Containing T Cell Activation Inhibitor 1) • NOS2 (Nitric Oxide Synthase 2)
    |
    KRAS mutation • KRAS G12D • KRAS G12V • RAS mutation • RAS wild-type • NRAS G12D • VTCN1 underexpression • VTCN1 overexpression • HRAS G12C
    over2years
    The pattern of KRAS mutations in non-small cell lung cancer (NSCLC): A retrospective study from south-eastern Georgia. (ASCO 2022)
    KRAS mutation subtypes have distinct genomic landscape which requires further assessment to guide future therapeutic development. In the geographical area of Augusta, Georgia, KRAS subtype G12V is as common as G12C.
    Retrospective data • MSi-H Biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    TP53 mutation • KRAS mutation • EGFR mutation • MSI-H/dMMR • KRAS G12C • BRAF mutation • KRAS G12V • MET mutation • KRAS G12 • HRAS G12C • KRAS expression
    3years
    Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. (PubMed, Mol Cancer)
    Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
    Review • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • NRAS mutation • HRAS mutation • KRAS G12 • HRAS G12C
    |
    Lumakras (sotorasib) • Krazati (adagrasib)
    over3years
    KRAS mutations in patients with colorectal cancer in Libya. (PubMed, Mol Clin Oncol)
    KRAS mutations were correlated with advanced age, with 10/13 being aged >50 years and affected 8/15 female patients (53%) compared with 5/19 male patients (26%). The highest frequency of KRAS mutations was observed in highly differentiated CRCs (8/13).
    Clinical • Journal
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • EGFR mutation • KRAS G12D • KRAS G12V • HRAS mutation • HRAS G12C
    over3years
    Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis. (PubMed, Small GTPases)
    NS1-expressing tumours were characterized by increased infiltration of CD4 + T helper cells. These results suggest that targeting the #x3B1;4-#x3B1;5 allosteric site of KRAS may represent a viable therapeutic approach for inhibiting KRAS-mutant pancreatic tumours.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CD4 (CD4 Molecule)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • HRAS mutation • HRAS G12C
    over3years
    [VIRTUAL] Increased neutrophil infiltration and lower prevalence of tumor mutation burden and microsatellite instability are hallmarks of RAS mutant colorectal cancers. (ASCO 2021)
    KRAS & NRAS mutations are associated with increased neutrophil abundance, with codon specific differences, while HRAS shows no difference . Overall CD8+ T cells and B cells are less abundant in KRAS & NRAS mutants; substantial variability was seen amongst different protein changes . RAS mutations were more prevalent overall than generally reported, but did not vary by age .
    Microsatellite instability • Tumor mutational burden • PD(L)-1 Biomarker • MSi-H Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CD8 (cluster of differentiation 8)
    |
    PD-L1 expression • KRAS mutation • TMB-H • MSI-H/dMMR • KRAS G12C • NRAS mutation • KRAS G12D • KRAS G12 • KRAS G13 • NRAS G12D • NRAS G13 • HRAS G12C
    over3years
    [VIRTUAL] Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer. (ASCO 2021)
    Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi . GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.
    Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ARID1A (AT-rich interaction domain 1A) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • MSH3 (MutS Homolog 3) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
    |
    PD-L1 expression • KRAS mutation • MSI-H/dMMR • KRAS G12C • BRAF mutation • PIK3CA mutation • BRAF V600 • HRAS mutation • KRAS G12 • NRAS Q61 • MAP2K1 mutation • NRAS G12 • KRAS Q61 • PIK3R1 mutation • HRAS G12C
    |
    MI Tumor Seek™
    almost4years
    [VIRTUAL] Landscape of driver mutations in MAPK/PI3K/AKT signaling pathways reveals insights into therapeutic targeting strategies (AACR 2021)
    The observed mutational profiles may explain some of the efficacy differences observed by targeting RAS across these diseases and have implications on acquired resistance mechanisms in a tissue-specific manner. Additional insights may be gleaned by investigating immunotherapy related biomarkers with these alterations to suggest combination strategies for effectively targeting the RAS signaling cascade.
    IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog) • mTOR (Mechanistic target of rapamycin kinase) • ARAF (A-Raf Proto-Oncogene)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • PTEN mutation • KRAS G12V • KRAS G13D • KRAS G12R • KRAS G12 • KRAS G13 • NRAS G12D • NRAS G13 • HRAS G12C
    almost4years
    Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts. (PubMed, Ann Oncol)
    An exception is Costello's syndrome, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway.
    Review • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • NF1 mutation • HRAS G12C
    over4years
    [VIRTUAL] Prevalence and clinical outcomes of non-small cell lung cancer (NSCLC) patients (pts) with potential pathogenic germline variants (pPGVs) in British Columbia (BC), Canada (ESHG 2020)
    Of 2074 pts, pPGVs were found in 83(4%), commonly BRCA1 (n=23), BRCA2 (n=29), MSH6 (n=8), MSH2 (n=5). 2 pts had pPGVs in both BRCA1 and BRCA2 . 33/83 pts(40%) were referred to genetics, 10 confirmed germline and 16 somatic.
    Clinical • Clinical data • BRCA Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • 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) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CCND1 (Cyclin D1) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • SMAD4 (SMAD family member 4) • PMS2 (PMS1 protein homolog 2) • BRCA (Breast cancer early onset) • CDH1 (Cadherin 1) • POLD1 (DNA Polymerase Delta 1) • CCND3 (Cyclin D3) • MUTYH (MutY homolog)
    |
    BRAF V600E • KRAS mutation • MSI-H/dMMR • KRAS G12C • BRAF V600 • KRAS G12 • EGFR mutation + KRAS mutation • BRCA mutation • HRAS G12C
    over4years
    [VIRTUAL] KRAS mutant epithelial ovarian carcinomas (EOC) represent distinct genomic genotypes (ESMO 2020)
    Legal entity responsible for the study: The authors. Funding: Has not received any funding.
    Tumor Mutational Burden • BRCA Biomarker • MSi-H Biomarker • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ARID1A (AT-rich interaction domain 1A) • BRCA (Breast cancer early onset) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • GNAS (GNAS Complex Locus)
    |
    KRAS mutation • BRCA2 mutation • TMB-H • MSI-H/dMMR • KRAS G12C • KRAS G12D • PTEN mutation • KRAS G12V • KRAS G12 • BRCA mutation • PIK3R1 mutation • HRAS G12C
    over4years
    A phase II trial of tipifarnib for patients with previously-treated, metastatic urothelial carcinoma harboring HRAS mutations. (PubMed, Clin Cancer Res)
    Oral tipifarnib resulted in manageable safety profile and encouraging antitumor efficacy against treatment-refractory UC containing HRAS mutations.
    Clinical • P2 data • Journal
    |
    STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    STK11 mutation • HRAS mutation • HRAS G13R • NRAS Q61R • NRAS G12 • HRAS G12S • HRAS G12C • HRAS Q61R • HRAS G13R
    |
    Zarnestra (tipifarnib)
    over4years
    Landscape of RAS Variations in 17,993 Pan-cancer Patients Identified by Next-generation Sequencing. (PubMed, Pathol Oncol Res)
    Our results suggested that a variety of solid tumors may harbor KRAS G12C/D/R/V mutation. These patients may benefit from KRAS inhibitors.
    Clinical • Journal • Pan Tumor
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D • HRAS G12C
    over4years
    [VIRTUAL] Combinations of SHP2 inhibitor to overcome RAS activation by receptor tyrosine kinases in response to ERK inhibition (AACR-II 2020)
    Experimental procedures: The combination efficacy and synergy of TNO155 with EGF816 (a 3rd generation EGFR inhibitor), dabrafenib+trametinib or a tool KRAS G12C inhibitor (G12Ci) were respectively assessed in a number of EGFR mutant lung cancer models, BRAFV600E colorectal cancer models and KRASG12C lung and colorectal cancer models. Our findings suggest that SHP2 inhibition is an effective strategy to block the feedback activation of wild type and G12C KRAS, as well as NRAS and HRAS, by a variety of RTKs, in response to ERK inhibition. Given the mutant selective properties of those inhibitors we studied, the tolerability of their combinations with TNO155 is highly expected. Our data provide pre-clinical rationale to explore those TNO155 combinations in the corresponding cancer indications in clinic.
    Late-breaking abstract
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    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • FGFR (Fibroblast Growth Factor Receptor) • PTPRT (Protein tyrosine phosphatase receptor type T)
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    BRAF V600E • KRAS mutation • EGFR mutation • KRAS G12C • BRAF V600 • MET amplification • EGFR C797S • KRAS amplification • NRAS G12 • BRAF mutation + MET amplification • EGFR T790M + KRAS mutation • HRAS G12C • BRAF amplification
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    Mekinist (trametinib) • Tafinlar (dabrafenib) • batoprotafib (TNO155) • nazartinib (EGF816)
    over4years
    [VIRTUAL] Landscape of RAS variations in 17993 solid tumors: a pan-cancer analysis. (ASCO 2020)
    AMG 510 which targeting KRAS G12C showed an ORR of 48% in patients with NSCLC... Our results suggested that a variety of solid tumors may harbor KRAS G12C/D/R/V mutation. These patients may benefit from KRAS inhibitors. Research Funding: None
    Pan tumor
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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 • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12 • NRAS G12D • HRAS G12C
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    Lumakras (sotorasib)
    almost5years
    [VIRTUAL] Prognostic effect of specific RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC). (ASCO 2020)
    "The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies."
    Clinical
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    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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    BRAF V600E • KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • HRAS mutation • KRAS G12 • HRAS G12C
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