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BIOMARKER:

KRAS Q61H

i
Other names: KRAS, KRAS1, KRAS2, Kirsten rat sarcoma viral oncogene homolog
Entrez ID:
Related biomarkers:
12d
Myxoid Inflammatory Myofibroblastic Sarcoma: Clinicopathologic Analysis of 25 Cases of a Distinctive Sarcoma With Deceptively Bland Morphology and Aggressive Clinical Behavior. (PubMed, Am J Surg Pathol)
The patient whose tumor harbored SEC31A::PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progression-free periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease.
Journal
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KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • TNFRSF8 (TNF Receptor Superfamily Member 8) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • JAK1 (Janus Kinase 1) • SEC31A (SEC31 Homolog A COPII Coat Complex Component)
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KRAS mutation • ALK rearrangement • KRAS G12V • TNFRSF8 expression • KRAS G12 • KRAS Q61H
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imatinib • sunitinib
14d
KRAS Allelic Variants in Biliary Tract Cancers. (PubMed, JAMA Netw Open)
This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.
Retrospective data • Journal • Tumor mutational burden • MSi-H Biomarker
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IFNG (Interferon, gamma)
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KRAS mutation • MSI-H/dMMR • NRAS mutation • KRAS G12D • KRAS G12V • TMB-L • KRAS G12 • NRAS Q61 • KRAS Q61H • NRAS G12D
14d
Exploring the Relationship Between KRAS, NRAS, and BRAF Mutations and Clinical Characteristics in Iranian Colorectal Cancer Patients. (PubMed, J Gastrointest Cancer)
The study's findings indicate a rising frequency of mutations in these genes in Iran, highlighting the need to screening mutations in the main exons of all three genes for effective colorectal cancer treatment strategies.
Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12 • NRAS Q61 • KRAS Q61H • KRAS exon 2 mutation • NRAS G12D • BRAF amplification • BRAF exon 15 mutation
1m
Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases. (PubMed, ESMO Open)
In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.
Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS wild-type • KRAS G12R • KRAS G12A • KRAS G12 • KRAS G12S • KRAS Q61H • KRAS A146T • KRAS A146V • KRAS G13A • KRAS G13C
1m
The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma. (PubMed, J Clin Med)
Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12 • KRAS Q61H
2ms
Structural insights into non-hotspot KRAS mutations and their potential as targets for effective cancer therapies. (PubMed, J Biomol Struct Dyn)
We further test whether FDA-approved KRAS inhibitors sotorasib and adagrasib successfully inhibit the E31D and E63K mutants. Based on sharp coherence in trajectories between wild KRAS and non-hotspot mutants, it is suggested that these novel mutants do not contribute to drug resistance mechanism. Overall, we provide a comprehensive understanding of the impact of non-hotspot mutations on KRAS and their potential as targets for effective cancer therapies.Communicated by Ramaswamy H. Sarma.
Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12C • KRAS G12D • RAS wild-type • KRAS G12 • KRAS Q61H
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Lumakras (sotorasib) • Krazati (adagrasib)
2ms
Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex. (PubMed, Life Sci Alliance)
Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.
Journal
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KRAS (KRAS proto-oncogene GTPase) • ARAF (A-Raf Proto-Oncogene) • LZTR1 (Leucine Zipper Like Transcription Regulator 1)
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KRAS mutation • KRAS G12D • KRAS G12 • NRAS Q61 • KRAS G13 • KRAS Q61H
3ms
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
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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 Q61K • NRAS Q61 • KRAS Q61H • NRAS G13 • NRAS Q61H • KRAS A146V • NRAS A146 • KRAS Q61K
3ms
Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120's Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines. (PubMed, Genes (Basel))
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.
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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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
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LY3009120
3ms
Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial. (PubMed, Front Oncol)
Patients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.
P2 data • Journal • Liquid biopsy • Metastases • Biopsy
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • GNAS (GNAS Complex Locus)
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BRAF V600E • KRAS mutation • NRAS mutation • BRAF wild-type • RAS mutation • NRAS Q61 • KRAS Q61H • BRAF mutation + RAS mutation
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oxaliplatin • irinotecan
6ms
Association of candidate alterations with primary resistance to KRAS G12D targeting in colorectal cancer. (ASCO-GI 2024)
KRAS G12D is associated with unique co-occurring molecular alterations compared to KRAS G12C in CRC. ctDNA-based NGS platforms can survey candidate alterations associated with primary resistance to KRAS G12D targeting in CRC. Further validation in preclinical models is needed.
Tumor mutational burden • MSi-H Biomarker
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • MSI (Microsatellite instability) • FGFR3 (Fibroblast growth factor receptor 3) • KEAP1 (Kelch Like ECH Associated Protein 1) • TACC3 (Transforming acidic coiled-coil containing protein 3) • SMAD4 (SMAD family member 4) • FBXW7 (F-Box And WD Repeat Domain Containing 7)
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BRAF V600E • KRAS mutation • MSI-H/dMMR • BRAF V600 • MET amplification • KRAS G12D • KRAS G12V • KEAP1 mutation • KRAS G12 • KRAS G13 • KRAS Q61H
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Guardant360® CDx
6ms
Frequency and oncologic outcomes of KRAS mutations in circulating tumor DNA of patients with pancreatic ductal adenocarcinoma. (ASCO-GI 2024)
Detection of KRAS mutation in liquid biopsies of patients with metastatic PDAC is associated with worse OS. KRAS G12D/Q61 alterations detection is associated with worse OS compared to other KRAS mutation subtypes. Ct-DNA detection of co-occurring CDKN2A mutation is associated with worse OS in patients with KRAS positive metastatic disease.
Clinical • Circulating tumor DNA
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • SMAD4 (SMAD family member 4)
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TP53 mutation • KRAS mutation • KRAS G12D • KRAS G12V • CDKN2A mutation • KRAS G12 • KRAS Q61H • KRAS Q61
8ms
Combinatory genomic and transcriptomic sequencing of Chinese KRAS mutant non-small cell lung cancer revealed molecular and inflammatory heterogeneity in tumor microenvironment (ESMO Asia 2023)
Conclusions Chinese KRAS mutant lung cancers are highly heterogeneous in terms of both KRAS mutations and co-altered genes and varied in inflammatory status in tumor microenvironment as well. Molecular and immune characteristics in KRASm NSCLC may influence the clinical outcome of adjuvant therapy.
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • LRP1B (LDL Receptor Related Protein 1B) • FAT1 (FAT atypical cadherin 1) • NOTCH3 (Notch Receptor 3) • ARID1B (AT-Rich Interaction Domain 1B) • ZFHX3 (Zinc Finger Homeobox 3) • SPTA1 (Spectrin Alpha) • SFTPA1 (Surfactant Protein A1)
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KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12A • KRAS G12 • KRAS Q61H
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TruSight Oncology 500 Assay
8ms
Interrogating real world tumor-infiltrating T-cell repertoires to identify antigen enriched TCRs in a large pan-cancer clinical cohort (SITC 2023)
Analysis of this resource – encompassing a diverse collection of cancer types, HLA genotypes, and mutational/viral contexts – revealed a subset of TCRs enriched with allele-specific neo-antigens. This dataset is a valuable resource for TCR therapeutic discovery, and can help identify naturally occuring TCRs that may minimize on-target, off-tumor toxicity.
Real-world evidence • Clinical • Pan tumor • Real-world
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
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KRAS Q61H
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Tempus xT Assay • Tempus xR
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
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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
10ms
Role of next-generation sequencing somatic assays in patients with advanced pancreatic cancer (ESMO 2023)
Conclusions Unfortunately, NGS somatic panel seems to have limited role for the PC treatment nowadays, with few pts receiving treatment guided by the panel. The development of new targeted therapy directed to the most frequently molecular alterations, including KRAS-directed therapy other than KRAS G12C, are urgently needed to improve outcomes.
Clinical • Next-generation sequencing • Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • Metastases
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • SMAD4 (SMAD family member 4) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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KRAS mutation • BRCA2 mutation • TMB-H • MSI-H/dMMR • KRAS G12C • KRAS G12D • PTEN mutation • KRAS G12V • KRAS G12R • KRAS G12A • KRAS G12 • KRAS Q61H
10ms
Validation of MET amplification using next-generation sequencing in lung adenocarcinoma (ESMO 2023)
Conclusions The detection of MET amplification by NGS did not show satisfactory concordance with the results obtained by FISH, likely due to the high heterogeneity in MET gene copy number enumeration. As a result, complementary determination by FISH is necessary, given the lack of standardized criteria for establishing CNAs positivity by NGS.
Next-generation sequencing
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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)
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KRAS G12C • EGFR L858R • MET amplification • MET exon 14 mutation • KRAS G12 • KRAS Q61H
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Oncomine Precision Assay
10ms
Tislelizumab Plus Platinum-Based Chemotherapy as First-Line Treatment for Advanced Lung Cancer with KRAS Mutation in China (IASLC-WCLC 2023)
The inhibitors AMG 510 and MRTX849 targeting the KRAS G12C mutation had shown promising results in clinical trials. This small sample retrospective study of real-world revealed that tislelizumab combined with nab-paclitaxel and platinum-based chemotherapy has shown a promising trend of anti-tumor efficacy with manageable safety profile for advanced lung cancer harboring KRAS mutations in China.Patients characteristicsCharacteristicsPatients (n=10)Age (median-yr)55 (51-69)<65 yr-no. (%)8 (80%)Male-no. (%)10 (100%)ECOG Performance Status 1-no.
Clinical • PD(L)-1 Biomarker • IO biomarker • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
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TP53 mutation • KRAS mutation • KRAS G12V • KRAS G12A • KRAS Q61H
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Tevimbra (tislelizumab) • Lumakras (sotorasib) • albumin-bound paclitaxel • Krazati (adagrasib)
10ms
Distant Metastasis Pattern and Baseline Clinicopathological Features from a Real-World KRAS G12C Mutant Cohort of Advanced NSCLC Patients (IASLC-WCLC 2023)
In our observational study the distribution of KRAS mutational status, its mutual exclusion with other concomitant driver mutations, and the strong association with smoking were consistent with data from literature. The G12C subgroup showed a different metastasis pattern with greater number of metastasis sites and higher incidence of brain metastases at the time of diagnosis compared to non-G12C patients. Despite the limited sample size, these results suggest that KRAS mutant patients represent a highly heterogeneous population and underline the need of better characterization of these patients to tailor treatment strategies.
Clinical • Real-world evidence • PD(L)-1 Biomarker • IO biomarker • Real-world • Metastases
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PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)
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PD-L1 expression • KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS wild-type • RAS wild-type • KRAS G12 • KRAS G13 • KRAS Q61H • KRAS G13C
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
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
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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
Detection of RAS gene mutations in patients with metastatic colorectal cancer during cetuximab-based first-line treatment and survival of the patients in relation to changes in RAS gene status (ESMO-GI 2023)
The first-line therapy consisted of anti-EGFR cetuximab in combination with irinotecan or oxaliplatin-based chemotherapy. PFS2 was statistically significantly shorter for RAS MT patients resulting in statistically non-significantly shorter OS in RAS MT patients. Our findings indicate that a change in RAS status is a negative prognostic factor for the second-line treatment, but this needs to be confirmed in large-scale studies. Testing RAS status analysing ctDNA might help to stratify patients during the metastatic treatment and to personalize the ongoing therapy.
Clinical • Metastases
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)
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KRAS mutation • NRAS mutation • KRAS G12D • RAS mutation • RAS wild-type • KRAS G12A • KRAS G12 • NRAS Q61 • KRAS Q61H • NRAS G12D • NRAS G12 • KRAS exon 3 mutation
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Idylla™ KRAS Mutation Test
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Erbitux (cetuximab) • oxaliplatin • irinotecan
1year
Characterizing KRAS allele variants within biliary tract cancers. (ASCO 2023)
KRAS mutations (mut) in BTC are associated with a poor prognosis; however, PD-L1 inhibition with Durvalumab may lead to an improved survival with KRAS mut (TOPAZ-1 trial)... This large series adds to the growing body of comprehensive genomic and immune landscape data of KRAS mut in BTC and will be of value in planning specific therapies in this heterogeneous group. Immune profiling studies are ongoing to further describe the immunophenotype of this subset.
Tumor mutational burden • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • SMAD4 (SMAD family member 4)
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TP53 mutation • KRAS mutation • MSI-H/dMMR • KRAS G12D • KRAS G12V • KRAS G12 • KRAS Q61H
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Imfinzi (durvalumab)
1year
RAS gene mutations and histomorphometric measurements in oral squamous cell carcinoma. (PubMed, Biotech Histochem)
Our findings suggest that KRAS may be mutated more frequently in OSCC compared to HRAS and NRAS. Also, the histological features of nuclear and cellular diameter differed significantly between the KRAS mutated and unmutated cases.
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • RAS (Rat Sarcoma Virus)
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KRAS mutation • RAS mutation • HRAS mutation • NRAS Q61 • KRAS G12S • KRAS Q61H • NRAS G12 • NRAS Q61L • HRAS Q61L • HRAS G12S • KRAS Q61L • NRAS G12S
1year
Biomarkers of acquired resistance to sotorasib (soto) plus panitumumab (pani) in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC) (AACR 2023)
"Of 21 pts with paired plasma samples, 17 (81%) had ≥1 acquired genomic alteration. RTK alterations and secondary (2°) RAS alterations were most common; each occurred in 57% of pts (Table). KRAS amplification was the most common single alteration (43%)."
Preclinical
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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)
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BRAF V600E • KRAS mutation • EGFR mutation • KRAS G12C • BRAF V600 • EGFR amplification • RAS mutation • NRAS Q61K • HER-2 S310F • KRAS G12 • NRAS Q61 • NRAS Q61R • KRAS Q61H • KRAS amplification • NRAS Q61L • EGFR G465R • EGFR S464L • KRAS Q61L
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Guardant360® CDx
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Vectibix (panitumumab) • Lumakras (sotorasib)
1year
Preclinical and clinical evaluation of the RAF/MEK clamp avutometinib (VS-6766) in combination with the mTOR inhibitor everolimus for the treatment of KRAS mutated non-small cell lung cancer (AACR 2023)
The combination of avutometinib and everolimus overcomes the activation of the PI3K/AKT/mTOR pathway which is an adaptive resistance mechanism to MAPK pathway inhibition. We have shown that avutometinib and everolimus induce synergistic anti-tumor effects preclinically, and preliminary data suggest clinically meaningful ORR and PFS in patients with KRAS mt NSCLC including non-G12C variants.
Preclinical • Combination therapy
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KRAS (KRAS proto-oncogene GTPase) • RPS6 (Ribosomal Protein S6) • AKT1S1 (AKT1 Substrate 1)
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KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12A • KRAS Q61H • KRAS G13A • KRAS G12C + KRAS G12V
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everolimus • avutometinib (VS-6766)
1year
RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target (AACR 2023)
As far as we are aware, RM-046 is the first oral and mutant-selective inhibitor of KRASQ61H(ON). It also represents an example of a non-covalent, mutant-selective tri-complex inhibitor of a KRAS oncogenic driver mutation.
Preclinical
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS wild-type • RAS mutation • RAS wild-type • NRAS Q61 • KRAS Q61H
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RMC-0708
over1year
Concordance of Actionable Mutations in Liquid Biopsies and Matched Tumor Tissue of Brazilian Non-small Cell Lung Cancer (NSCLC) (LALCA 2023)
The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.
Liquid biopsy • Biopsy • Discordant
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EGFR (Epidermal growth factor receptor) • 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) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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KRAS G12C • EGFR T790M • KRAS G12D • KRAS G12V • KRAS G13D • KRAS G12 • PIK3CA E542K • KRAS G13 • TP53 R175H • KRAS Q61H • ALK R1275Q • BRAF G469A • EGFR E709K • MAP2K1 P124Q • PIK3CA E542 • TP53 R248Q • TP53 Y220C • EGFR E746 • MAP2K1 E203K • MAP2K1 P124 • TP53 R273C
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Oncomine™ Lung cfDNA Assay
over1year
Characterization of Homologous Recombination Deficiency-Associated Pancreatic Ductal Adenocarcinoma Using Oncomine Comprehensive Assay Plus NGS-Based Cancer Panel (USCAP 2023)
In contrast to 14.5-16.5% through NGS panels and 24-44% through WES or WGS reported in the literatures, our HRD assessment using Oncomine Plus NGS-based cancer panel revealed a high prevalence of 33% in our PDAC cohort, suggesting NGS-based panel method could be a potential powerful tool for HRD estimate. Interestingly, our HRD-associated PDAC cohort showed a different distribution of concurrent variants compared to TCGA PDAC, which might be suggestive of the biologic differences between HRD-associated PDAC cohort and non-HRD-associated PDAC cohort.
Tumor mutational burden • PARP Biomarker • MSi-H Biomarker • BRCA Biomarker • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • PALB2 (Partner and localizer of BRCA2) • RNF43 (Ring Finger Protein 43) • CDK12 (Cyclin dependent kinase 12) • SMAD4 (SMAD family member 4) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • MRE11A (MRE11 homolog, double strand break repair nuclease) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCF (FA complementation group F) • FANCL (FA Complementation Group L) • HDAC2 (Histone deacetylase 2) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
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KRAS mutation • TMB-H • MSI-H/dMMR • HRD • KRAS Q61H
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Oncomine™ Comprehensive Assay Plus
over1year
Impact of KRAS mutation variants on clinicopathological features and outcomes in patients with metastatic pancreatic adenocarcinoma. (ASCO-GI 2023)
No significant difference was observed in metastatic PDAC with KRAS mutations compared to WT. However, numerical difference in OS were observed among the various KRAS mutation type. Hence, larger studies are needed to better define the effect of KRAS type on outcomes.
Clinical • Metastases
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12D • KRAS G12V • KRAS wild-type • RAS wild-type • KRAS Q61H
over1year
Clinical Significance of Somatic Mutations in RAS/RAF/MAPK Signaling Pathway in Moroccan and North African Colorectal Cancer Patients. (PubMed, Asian Pac J Cancer Prev)
RAS mutations could be useful in future target anti-EGFR therapy and molecular CRC screening strategy in Morocco.
Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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KRAS mutation • BRAF mutation • NRAS mutation • KRAS G12D • KRAS G12V • KRAS wild-type • RAS mutation • NRAS Q61 • KRAS G12S • NRAS Q61R • KRAS Q61H • KRAS exon 2 mutation • NRAS G12D • NRAS G13 • NRAS Q61L • KRAS G13A • KRAS Q61L • NRAS G12S
over1year
KRAS in NSCLC: State of the Art and Future Perspectives. (PubMed, Cancers (Basel))
Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
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TP53 mutation • KRAS mutation • KEAP1 mutation • KRAS Q61H
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Lumakras (sotorasib) • Krazati (adagrasib) • divarasib (RG6330)
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
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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)
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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
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Cotellic (cobimetinib) • Ninlaro (ixazomib) • dexamethasone • pomalidomide
over1year
Therapeutic Outcomes and Clinical Features of Advanced Non-Small Cell Lung Cancer Carrying KRAS Mutations: A Multicenter Real-life Retrospective Study. (PubMed, Clin Lung Cancer)
Here, we report on real-life data from a large retrospective cohort of advanced NSCLC harbouring KRAS alterations, with particular attention to G12C mutation. Our study offers useful clues on survival outcome, therapeutic response and clinico-pathological correlations in KRAS-mutant setting, especially in the upcoming era of KRAS G12C targeting therapy.
Retrospective data • Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12C • KRAS G12 • KRAS Q61H
over1year
Identification of IKZF1 Exon Skipping by a Custom Designed Targeted NGS Assay (AMP 2022)
IKZF1 exon skipping isoforms were reliably identified by our RNA-based NGS assay. Further studies are warranted on the morphologic and clinical correlation, the clinical relevance of IKZF1 exon skipping with coexisting aberrations, and the prognostic effect of low positive IKZF1 exon skipping.
Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IKZF1 (IKAROS Family Zinc Finger 1) • JAK1 (Janus Kinase 1)
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NRAS mutation • KRAS G12D • KRAS G12 • NRAS Q61 • KRAS Q61H • NRAS G12D • ABL1 T315I • IKZF1 deletion
over1year
ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer. (PubMed, Int J Cancer)
Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response...In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials.
Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • EPHA6 (EPH Receptor A6) • MCM9 (Minichromosome Maintenance 9 Homologous Recombination Repair Factor) • SRPK1 (SRSF Protein Kinase 1)
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KRAS mutation • ROS1 fusion • ROS1 rearrangement • KRAS Q61H • ROS1 wild-type
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Xalkori (crizotinib)