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    BIOMARKER:

    KRAS Q61K

    i
    Other names: KRAS, KRAS1, KRAS2, Kirsten rat sarcoma viral oncogene homolog
    Entrez ID:
    3845
    Related biomarkers:
    Expression
    Mutation
    CNA
    Others
    19d
    Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II. (PubMed, Eur J Cell Biol)
    This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • NRAS mutation • RAS mutation • NRAS Q61K • NRAS Q61 • NRAS Q61R • HRAS Q61R • KRAS Q61K
    2ms
    Computational Exploration of Single-Nucleotide Polymorphisms in the Human hRAS Gene: Implications and Insights. (PubMed, Cureus)
    Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    NRAS Q61K • NRAS Q61 • KRAS Q61H • NRAS G13 • NRAS Q61H • KRAS A146V • NRAS A146 • KRAS Q61K
    4ms
    Low incidence of BRAF and NRAS mutations in a population with a high incidence of melanoma. (PubMed, Virchows Arch)
    Demographic details, tumor characteristics, and 10-year outcome data were also obtained.Ten cases with BRAF V600E mutations (11.6%) and five (5.49%) NRAS mutations (4 at Q61R, 1 at Q61K) were detected. No statistically significant differences were noted between groups for age, gender, depth of invasion, nodal status, or recurrence status (p ≥ 0.05).These findings suggest that the Irish population has a markedly lower incidence of BRAF and NRAS mutations in melanoma than those reported in other cohorts.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    BRAF V600E • KRAS mutation • BRAF mutation • NRAS mutation • BRAF V600 • KIT mutation • NRAS Q61K • NRAS Q61 • NRAS Q61R • NRAS mutation + BRAF mutation • KRAS Q61K
    5ms
    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
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability)
    |
    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
    8ms
    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
    |
    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)
    |
    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
    |
    Nerlynx (neratinib) • pemetrexed
    9ms
    The integrated genomic and epigenomic landscape of gangliogliomas - retrospective analysis of a single-centre case series (ECP 2023)
    One case presented with concerning copy number changes and TERT promoter mutation, raising the possibility of glioblastoma. Further studies regarding the biological behaviour of these tumours are needed.
    Retrospective data
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • TERT (Telomerase Reverse Transcriptase) • KIAA1549 • SHTN1 (Shootin 1)
    |
    BRAF V600E • KRAS mutation • BRAF V600 • NTRK2 fusion • FGFR2 mutation • BRAF wild-type • FGFR2 fusion • KIAA1549-BRAF fusion • BRAF fusion • FGFR3 fusion • TERT mutation • TERT promoter mutation • KRAS Q61K
    10ms
    Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma. (PubMed, Hematol Oncol)
    Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone.
    Clinical data • Journal • Tumor mutational burden
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • FGFR3 (Fibroblast growth factor receptor 3) • CCND1 (Cyclin D1) • IRF4 (Interferon regulatory factor 4) • PRDM1 (PR/SET Domain 1) • NT5C (5', 3'-Nucleotidase, Cytosolic) • TENT5C (Terminal Nucleotidyltransferase 5C) • EGR1 (Early Growth Response 1)
    |
    TP53 mutation • KRAS mutation • BRAF mutation • NRAS mutation • KRAS wild-type • RAS wild-type • NRAS Q61K • NRAS Q61 • NRAS wild-type • KRAS Q61K
    |
    lenalidomide • bortezomib • dexamethasone
    11ms
    A Shift in Molecular Drivers of Papillary Thyroid Carcinoma Following the 2017 WHO Classification: Characterization of 554 Consecutive Tumors with Emphasis on BRAF-Negative Cases. (PubMed, Mod Pathol)
    Driver gene fusions were identified in 8.5% of PTCs and were clinically relevant given the emerging targeted kinase inhibitor therapy. Of the 1.6% of cases for which no driver alteration was detected, the specificity of drivers tested and tumor classification require further investigation.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    BRAF V600E • BRAF V600 • NTRK1 fusion • NTRK3 fusion • RET fusion • ALK fusion • RAS mutation • NRAS Q61K • NRAS Q61 • BRAF fusion • NRAS Q61R • FGFR1 fusion • HRAS Q61R • KRAS Q61K
    |
    FusionPlex® Pan Solid Tumor v2 panel
    1year
    RAS-mutations in population-based and real-life metastatic colorectal cancer cohorts (ESMO-GI 2023)
    In this cohort with population-based and real-world patients, no differences in patient characteristics or treatment modalities were seen between different RAS mt, except a higher frequency of right-colon primaries among KRAS mt compared with NRAS mt. KRAS -G12S conferred a worse OS compared with some other KRAS mt, whereas no other differences in OS were seen. It therefore seems as if different RAS mt behave quite similar.
    Clinical • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • NRAS mutation • BRAF V600 • KRAS G12D • KRAS G12V • RAS mutation • NRAS Q61K • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS G12S • NRAS Q61R • KRAS G13 • KRAS Q61H • NRAS G12D • NRAS G12 • NRAS G13 • KRAS A146T • NRAS A146T • NRAS A146 • KRAS G12C + KRAS G12V • KRAS Q61K • NRAS G12S
    1year
    KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas. (PubMed, Int J Mol Sci)
    Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability)
    |
    KRAS mutation • HER-2 overexpression • BRAF mutation • HER-2 amplification • NRAS mutation • NRAS Q61K • NRAS Q61 • KRAS Q61K
    1year
    DCC-3084, a RAF dimer inhibitor, broadly inhibits BRAF class I, II, III, BRAF fusions, and RAS-driven solid tumors leading to tumor regression in preclinical models (AACR 2023)
    The Switch Control inhibitor DCC-3084 broadly inhibits Class I, II and III BRAF mutations, BRAF fusions, and BRAF/CRAF heterodimers leading to tumor regression in preclinical models. The overall preclinical profile of DCC-3084 supports IND-enabling activities towards clinical development in a key area of unmet medical need in RAS and RAF mutant cancers.
    Preclinical
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene)
    |
    KRAS mutation • KRAS G12C • BRAF mutation • BRAF V600 • RAS mutation • BRAF fusion • KRAS Q61K
    |
    DCC-3084
    over1year
    Afirma Genomic Sequencing Classifier with Afirma Xpression Atlas Results on Thyroid Nodules (USCAP 2023)
    Afirma XA detected abnormalities in approximately one-third of Afirma GSC suspicious nodules, of which RAS mutations were the most common finding (68%). Two-thirds of cases labeled suspicious by Afirma GSC did not reveal gene mutations or fusions by Afirma XA testing, suggesting other unknown genetic alterations requiring further investigation.
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • HRAS (Harvey rat sarcoma viral oncogene homolog) • ETV6 (ETS Variant Transcription Factor 6) • RAS (Rat Sarcoma Virus) • DICER1 (Dicer 1 Ribonuclease III) • PPARG (Peroxisome Proliferator Activated Receptor Gamma) • PAX8 (Paired box 8) • TBL1XR1 (TBL1X Receptor 1)
    |
    BRAF V600E • BRAF V600 • KRAS G12V • RAS mutation • RET mutation • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS Q61R • NRAS G12 • HRAS Q61R • KRAS Q61K
    |
    Afirma® Genomic Sequencing Classifier
    over1year
    Characterization of Molecular Divers in 554 Consecutive Papillary Thyroid Carcinomas in a Post-2017 WHO Classification Cohort (USCAP 2023)
    In this post-2017 WHO classification cohort of 554 consecutive PTCs, BRAF V600E mutation is highly prevalent in 87% of the cases. RAS mutations account for only 1.1% of the cases and half of them are classified as encapsulated follicular variant of PTC. Kinase gene fusions are identified in 8.5% of the cases and are clinically relevant given the emerging targeted kinase inhibitor therapy.
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • FGFR1 (Fibroblast growth factor receptor 1) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • NTRK1 fusion • NTRK3 fusion • RET fusion • ALK fusion • RAS mutation • NRAS Q61K • HRAS mutation • NRAS Q61 • BRAF fusion • NRAS Q61R • FGFR1 fusion • NTRK1 mutation • HRAS Q61R • KRAS Q61K
    |
    FusionPlex® Pan Solid Tumor v2 panel • VENTANA anti-BRAF V600E (VE1) Mouse Monoclonal Primary Antibody
    over1year
    Mutation status of full RAS and BRAF in 169 Moroccan patients with colorectal cancer. (ASCO-GI 2023)
    Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology in Morocco. This approach may be able to significantly reduce the burden of disease in the country. Moreover, the Moroccan government should develop policy on CRC prevention and public health programs which may serve as a feasible setting to increase public awareness on lifestyle risk factors.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
    |
    BRAF V600E • KRAS mutation • KRAS G12C • BRAF mutation • NRAS mutation • BRAF V600 • KRAS G12D • RAS mutation • NRAS Q61K • KRAS G12 • NRAS Q61 • KRAS exon 2 mutation • NRAS G12D • NRAS G13 • KRAS exon 3 mutation • KRAS exon 4 mutation • KRAS Q61K
    |
    Idylla™ BRAF Mutation Test • Idylla™ KRAS Mutation Test
    over1year
    CRISPR/Cas9 Edited RAS & MEK Mutant Cells Acquire BRAF and MEK Inhibitor Resistance with MEK1 Q56P Restoring Sensitivity to MEK/BRAF Inhibitor Combo and KRAS G13D Gaining Sensitivity to Immunotherapy. (PubMed, Cancers (Basel))
    Interestingly, the KRAS G13D isogenic line displays elevated PD-L1 expression suggesting the KRAS G13D mutation could be a potential indication for immunotherapy. Overall, these three novel isogenic cell models with endogenous level RAS and MEK1 point mutations provide direct bio-functional evidence demonstrating that acquiring a drug-resistant gene drives tumor cell survival and may simultaneously introduce new indications for combo therapy or immunotherapy in the clinic.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    PD-L1 expression • BRAF V600E • KRAS mutation • BRAF mutation • BRAF V600 • EGFR overexpression • KRAS G13D • RAS mutation • NRAS Q61K • NRAS Q61 • KRAS G13 • NRAS G13 • NRAS G13D • KRAS Q61K • KRAS expression
    over1year
    Myeloma Developing Regimens Using Genomics (MyDRUG): Longitudinal Single-Cell Transcriptional Landscape of the Myeloma and Immune Microenvironment in Relapsed/Refractory Multiple Myeloma Patients Treated with MEK-Inhibitor, Cobimetinib (ASH 2022)
    Cobimetinib plus Dexamethasone were administered for two 28-day cycles followed by the addition of an Ixazomib, Pomalidomide and Dexamethasone (IPd) backbone therapy for all subsequent treatment cycles until disease progression. After exposure to Cobimetinib, the plasma cell clusters that expressed higher levels of this MAPK signature decreased in proportion relative to clusters with lower expression of MAPK. In summary, here we report on our initial observations of dynamic transcriptional changes in specific immune and myeloma cell compartments that are associated with targeting the MAPK pathway in the MyDrug C1 sub-protocol.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • FGFR3 (Fibroblast growth factor receptor 3) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • SDC1 (Syndecan 1) • CD14 (CD14 Molecule) • CDKN2C (Cyclin Dependent Kinase Inhibitor 2C)
    |
    BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • KRAS G12V • NRAS Q61K • KRAS G12 • NRAS Q61 • MAP2K1 mutation • NRAS Q61R • KRAS Q61H • NRAS G12 • KRAS Q61K • NRAS G12V
    |
    Cotellic (cobimetinib) • Ninlaro (ixazomib) • dexamethasone • pomalidomide
    2years
    Phase I trial of the RAF/MEK clamp VS-6766 in combination with everolimus using an intermittent schedule with expansion in NSCLC across multiple KRAS variants. (ASCO 2022)
    A tolerable intermittent dosing schedule targeting both the MAPK and PI3K pathways has been established. The combination of VS-6766 with everolimus has shown activity in patients with a variety of KRAS mutation variants including responses in KRAS mt NSCLC.
    P1 data • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    KRAS mutation • KRAS G12D • KRAS G12V • NRAS Q61K • KRAS G12 • NRAS Q61 • KRAS G13 • NRAS G12D • NRAS G13 • KRAS G13A • KRAS Q61K
    |
    everolimus • avutometinib (VS-6766)
    2years
    Natural distribution of genomic alterations correlated with the resistance to KRASG12C inhibitor in Chinese colorectal cancer. (ASCO 2022)
    Novel acquired secondary KRAS mutations within the adagrasib-binding pocket such as Y96C, H95D/Q/R, R68S, 2... Our analysis results indicate about 15% KRAS G12C-mutant Chinese CRC were probable resistant to KRASG12C inhibitor. One-third of these patients had co-existed oncogenic fusions and higher TMB levels, suggesting possibilities for other therapeutic choices.
    Tumor Mutational Burden
    |
    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) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NRG1 (Neuregulin 1) • TACC3 (Transforming acidic coiled-coil containing protein 3) • ETV6 (ETS Variant Transcription Factor 6) • EWSR1 (EWS RNA Binding Protein 1) • IKZF3 (IKAROS Family Zinc Finger 3) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • GRB7 (Growth Factor Receptor Bound Protein 7) • TCF7L2 (Transcription Factor 7 Like 2) • TPM4 (Tropomyosin 4) • PAX7 (Paired Box 7)
    |
    TP53 mutation • BRAF V600E • KRAS mutation • TMB-H • PIK3CA mutation • BRAF V600 • MET amplification • KRAS G12D • ALK fusion • NRAS Q61K • NRAS Q61 • KRAS Q61H • NRAS G12D • FGFR3 fusion • NRAS G13 • MAP2K1 K57T • FGFR3 amplification • KRAS Q61K
    |
    Krazati (adagrasib)
    2years
    CASE OF AN EMBRYONAL RHABDOMYOSARCOMA IN A PEDIATRIC PATIENT: THERAPEUTIC TARGET IDENTIFICATION (ASPHO 2022)
    The analyses revealed important takeaways: 1) key activating mutations can be identified using a simple liquid biopsy, 2) some embryonal RMS cases have PD-L1 expression, and 3) OncoSignal analysis may be useful in identifying oncogenic driver pathways. These findings helped to identify that this child was eligible for a clinical trial that contained combined MEK and PD-L1 checkpoint inhibitors, a potential solution to treating embryonal RMS.
    Clinical • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • 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) • FGFR4 (Fibroblast growth factor receptor 4) • PAX3 (Paired Box 3) • PAX7 (Paired Box 7)
    |
    PD-L1 expression • TP53 mutation • KRAS mutation • NRAS mutation • PIK3CA mutation • EGFR amplification • NRAS Q61K • NRAS Q61 • KRAS Q61K
    |
    Follow It® • OncoSignal™
    2years
    Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in cholangiocarcinoma with FGFR fusions/rearrangements (AACR 2022)
    We sought to investigate mechanisms of acquired resistance to FGFRi and approaches to overcome resistance. Longitudinal plasma samples were collected from patients with FGFR pathway alterations enrolled in the futibatinib phase I trial (NCT02052778) and sequenced using a targeted, 73-gene panel... Convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi therapy. Work is ongoing to determine if targeting co-alterations may enhance the efficacy of FGFRi in FGFR2-fusion driven malignancies.
    Preclinical
    |
    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)
    |
    BRAF V600E • KRAS mutation • BRAF V600 • KRAS G12D • FGFR2 mutation • FGFR2 fusion • FGFR fusion • NRAS Q61K • KRAS G12 • NRAS Q61 • FGFR2-BICC1 fusion • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • NRAS G13D • KRAS Q61K • BRAF V600E + KRAS G12D • NRAS G12C
    |
    Lytgobi (futibatinib)
    2years
    Molecular landscape of osimertinib resistance in patients and patient-derived preclinical models. (PubMed, Ther Adv Med Oncol)
    A patient-derived xenograft established from osimertinib-resistant patient revealed KRAS p.G12D mutation which could be overcome with combination of osimertinib, trametinib, and buparlisib. In this study, we explored the genetic profiles of osimertinib-resistant NSCLC patient samples using targeted deep sequencing. In vitro and in vivo models harboring osimertinib resistance revealed potential novel treatment strategies after osimertinib failure.
    Preclinical • Journal
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • EP300 (E1A binding protein p300)
    |
    KRAS mutation • EGFR mutation • BRAF mutation • PIK3CA mutation • KRAS G12D • EGFR C797S • ALK mutation • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS G12D • KRAS Q61K
    |
    Mekinist (trametinib) • Tagrisso (osimertinib) • buparlisib (AN2025)
    over2years
    Clinical, Pathological, and Molecular Features of Papillary Renal Cell Neoplasm with Reverse Polarity: A Review of 196 Papillary Renal Cell Carcinomas (USCAP 2022)
    Papillary renal cell neoplasm with reverse polarity represents 3.57% of PRCC in our study. PRNRP is a distinct and rare entity with characteristic morphological features and frequent mutation in KRAS genes. The positivity of GATA3 and L1CAM support that this tumor arises from the distal renal ducts.
    Review • Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • VIM (Vimentin) • MME (Membrane Metalloendopeptidase) • GATA3 (GATA binding protein 3) • L1CAM (L1 cell adhesion molecule) • PAX8 (Paired box 8)
    |
    KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • KRAS G12S • VIM expression • KRAS Q61K
    |
    Idylla™ KRAS Mutation Test
    over2years
    [VIRTUAL] Mutation Detection in Circulating Tumor Cells at the SingleCell Level Using the MassARRAY System (AMP 2021)
    We have established a novel, straightforward protocol to detect mutation directly from CTC without preamplification at the single cell level. We expect that this workflow will facilitate the exploration of genetic content of CTC, thereby increasing its potential use in the clinic
    Circulating tumor cells
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
    |
    BRAF V600E • NRAS mutation • BRAF V600 • EGFR T790M • PIK3CA H1047R • KRAS G12V • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS Q61R • MAP2K1 P124S • MAP2K1 C121S • KRAS Q61K • MAP2K1 P124 • CDK4 mutation
    |
    CELLSEARCH® • Parsortix Liquid Biopsy
    over2years
    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.
    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)
    over2years
    Clinicopathologic and Survival Correlates of Embryonal Rhabdomyosarcoma Driven by RAS/RAF Mutations. (PubMed, Genes Chromosomes Cancer)
    In conclusion, RAS mutations occur in 27% of ERMS, with NRAS mutations encompassing half of the cases. Overall RAS-mutant RMS do not correlate with age or site, but most tumors show an undifferentiated and spindle cell morphology.
    Clinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • NRAS Q61K • HRAS mutation • KRAS G12 • NRAS Q61 • NRAS G12D • NRAS G12 • KRAS Q61K
    almost3years
    Osimertinib-resistant NSCLC cells activate ERBB2 and YAP/TAZ and are killed by neratinib. (PubMed, Biochem Pharmacol)
    We performed additional mechanistic analyses to redefine neratinib biology and determined the mechanisms by which the multi-kinase inhibitor neratinib interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing either mutant KRAS (G12S; Q61H; G12A; G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M; exon 19 deletion)...Afatinib or osimertinib resistant cells were killed with a similar efficacy to non-resistant cells...Thus, neratinib targets an unidentified protein whose functional inhibition directly results in RAS inactivation and tumor cell killing. Our data prove that, albeit indirectly, oncogenic RAS proteins are druggable by neratinib.
    Journal
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    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • JAK2 (Janus kinase 2) • STAT3 (Signal Transducer And Activator Of Transcription 3)
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    KRAS mutation • KRAS G12C • NRAS mutation • EGFR L858R • EGFR T790M • KRAS G12V • NRAS Q61K • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS G12S • KRAS Q61H • NRAS G12 • EGFR H1975 • KRAS Q61K • KRAS deletion • NRAS G12S • TYMS expression • KRAS expression
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    Tagrisso (osimertinib) • Gilotrif (afatinib) • Nerlynx (neratinib) • pemetrexed
    3years
    [VIRTUAL] Mechanisms of acquired resistance to KRAS G12C inhibition in cancer (AACR 2021)
    In early phase clinical trials of patients with KRASG12C-mutant cancers, promising antitumor activity has been reported with drugs such as adagrasib (MRTX849) and sotorasib (AMG510) which are direct inhibitors of KRASG12C. Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors in patients with cancer. Acquired genomic mutations, amplifications, and rearrangements may be potentially targetable by combining KRASG12C inhibition with available kinase inhibitors or SHP2 inhibitors.
    Preclinical • Late-breaking abstract
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    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • FGFR (Fibroblast Growth Factor Receptor)
    |
    BRAF V600E • KRAS mutation • EGFR mutation • NRAS mutation • BRAF V600 • MET amplification • EGFR amplification • KRAS G13D • NRAS Q61K • RET M918T • NRAS Q61 • KRAS G13 • KRAS amplification • NRAS G13 • BRAF amplification • KRAS Q61K • MAP2K1 K57N
    |
    Lumakras (sotorasib) • Krazati (adagrasib)
    3years
    [VIRTUAL] Papillary Renal Neoplasm with Reverse Polarity. Expanding the Molecular and Immunohistochemical Features (USCAP 2021)
    In our series we recorded a strong expression of parvalbumin in all PRNRPs, along with a new undescribed mutation of the KRAS gene. Hence our findings both strengthen the hypothesis of a distal nephron differentiation of PRNRPs and widen the current knowledge on the molecular biology of this newly discovered renal neoplasm.
    KRAS (KRAS proto-oncogene GTPase) • GATA3 (GATA binding protein 3)
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    KRAS mutation • KRAS G12V • KRAS G12 • KRAS Q61K • KRAS expression
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    Idylla™ KRAS Mutation Test
    over3years
    Mutation-specific effects of NRAS oncogenes in colorectal cancer cells. (PubMed, Adv Biol Regul)
    To elucidate specific functions of NRAS mutations in CRC, we expressed doxycycline-inducible G12D and Q61K mutations in the CRC cell line Caco-2...In addition, RNA sequencing results indicated activation of the IL1-, JAK/STAT-, NFκB- and TNFα signalling pathways. These results form the basis for an NRAS-driven inflammatory phenotype in CRC.
    Journal
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    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • IL1A (Interleukin 1, alpha)
    |
    KRAS mutation • NRAS mutation • KRAS G12D • NRAS Q61K • NRAS Q61 • NRAS G12D • NRAS G12 • KRAS Q61K • KRAS expression
    over3years
    NRAS mutant E132K identified in young-onset sporadic colorectal cancer and the canonical mutants G12D and Q61K affect distinct oncogenic phenotypes. (PubMed, Sci Rep)
    The results highlight the need to characterize isoform- and mutation-specific oncogenic phenotypes which can have repercussions in disease management and choice of therapeutic intervention. Further analyses of young-onset versus late-onset CRC datasets are necessary to qualify NRAS E132K as a biomarker for the young-onset subtype.
    Journal
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    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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    KRAS mutation • NRAS mutation • KRAS G12D • NRAS Q61K • KRAS G12 • NRAS Q61 • NRAS G12D • NRAS G12 • KRAS Q61K
    over3years
    [VIRTUAL] ADENOCARCINOMA OF THE LUNG WITH A MILIARY PATTERN (CHEST 2020)
    Immuno-chemotherapy with a combination of carboplatin, pemetrexed, and pembrolizumab was initiated, given his stage IV metastatic lung adenocarcinoma. The differential diagnosis for miliary patterns on chest imaging includes tuberculosis, fungal infections, sarcoidosis, pneumoconiosis, and secondary metastasis...Our case is of interest given the negative TTF-1 with a KRAS Q61K mutation, the later of which is associated with resistance to the EGFR inhibitors gefitinib and erlotinib... The initial radiologic presentation of these cases can be misleading in areas with high prevalence of infections such as tuberculosis and fungal infections. The possibility of primary lung cancer should also be considered in these cases.
    PD(L)-1 Biomarker
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    KRAS (KRAS proto-oncogene GTPase) • NKX2-1 (NK2 Homeobox 1) • CDX2 (Caudal Type Homeobox 2) • NAPSA (Napsin A Aspartic Peptidase)
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    KRAS Q61K
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    Keytruda (pembrolizumab) • erlotinib • carboplatin • gefitinib • pemetrexed