News - KRAS G13C - LARVOL VERI

Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells. (PubMed, Stem Cell Res Ther)

Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.

5 days ago

Journal • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)

KRAS mutation • KRAS wild-type • RAS mutation • RAS wild-type • KRAS G13 • KRAS G13C

12d

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.

12 days ago

Journal

KRAS (KRAS proto-oncogene GTPase)

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

Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement. (PubMed, Anal Chem)

We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

1 month ago

Journal

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12C • KRAS G12D • KRAS wild-type • RAS wild-type • KRAS G12 • KRAS G13C

3ms

Real-world clinical utility of next-generation sequencing ctDNA for patients with advanced lung squamous cell carcinoma (ELCC 2024)

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

3 months ago

Real-world evidence • Clinical • Next-generation sequencing • Circulating tumor DNA • Real-world • Metastases

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • FGFR1 (Fibroblast growth factor receptor 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A)

TP53 mutation • BRAF V600E • BRAF V600 • EGFR exon 19 deletion • KRAS G12D • EGFR amplification • KRAS G12V • FGFR1 amplification • ALK fusion • KRAS G12R • KRAS G12A • KRAS G12 • KRAS G13 • KRAS amplification • FGFR1 fusion • NRAS G12 • NRAS G13 • KRAS G13C • EGFR fusion • KRAS G61 • KRAS deletion

InVisionFirst®-Lung

8ms

BRAF Mutation Heterogeneity Detected Using Circulating Tumor DNA Sequencing in Synchronous Colon Cancer: A Case Report. (PubMed, Cancer Diagn Progn)

Next, we performed next-generation sequencing on circulating tumor DNA from the patient's plasma (Foundation One Liquid CDx), which revealed the V600E mutation of BRAF, suggesting that there was genetic heterogeneity among the synchronized primary lesions, one of which was responsible for the chemo-refractory rapid-growing liver metastases. Genetic profiling with liquid biopsy at the time of recurrence and metastasis may be useful in patients with multiple synchronous cancers because there is less heterogeneity between primary and metastatic sites.

8 months ago

Journal • MSi-H Biomarker • Circulating tumor DNA

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability)

BRAF V600E • MSI-H/dMMR • BRAF mutation • BRAF V600 • BRAF wild-type • KRAS G13 • KRAS G13C

FoundationOne® Liquid CDx

8ms

A Case of Rosai‑Dorfman Disease, Associated With KRAS 13C, POLE, and NDE1 Mutations, Masquerading as Chronic Myelomonocytic Leukemia: Complex Management Paradigm (SOHO 2023)

A 57-year-old man with RDD developed worsening cytopenias and respiratory distress after his initial response to rituximab, steroids, and lenalidomide. NGS is likely to be helpful for the work-up and management of RDD. We found potential novel therapeutic targets in RDD, such as KRAS G13C and POLE mutations.

8 months ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • POLE (DNA Polymerase Epsilon)

KRAS mutation • POLE mutation • KRAS G13 • KRAS G13C

Rituxan (rituximab) • lenalidomide

9ms

RAS-precision medicine trans-atlantic partnership: Comparative analysis of KRAS codon 12 and 13 mutations in non-small cell lung cancer (ESMO 2023)

These preclinical results indicate unique therapeutic vulnerabilities across allelic subgroups. RNA-sequencing and kinome profiling will allow us to further characterise these mutations in NSCLC.

9 months ago

Licensing / partnership

KRAS (KRAS proto-oncogene GTPase) • NF1 (Neurofibromin 1) • RAS (Rat Sarcoma Virus)

KRAS mutation • KRAS G12C • KRAS G12D • KRAS wild-type • NF1 mutation • KRAS G13D • RAS wild-type • KRAS G12 • KRAS G13 • KRAS G13C • EPCAM expression • KRAS expression

9ms

Prevalence of KRAS Subtype Alterations in Non-Small Cell Lung Cancer (NSCLC) with Brain Metastases (IASLC-WCLC 2023)

This study details the most prevalent KRAS alterations and co-mutations among KRASalt NSCLC. KRAS p.G12C was the most frequently observed alteration and co-mutations were found in TP53, LRP1B, STK11, KEAP1, and CDKN2A. Our findings have therapeutic implications as co-alterations with STK11/KEAP1 are associated with worse outcomes.

9 months ago

PD(L)-1 Biomarker • IO biomarker

EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • KEAP1 (Kelch Like ECH Associated Protein 1) • LRP1B (LDL Receptor Related Protein 1B)

PD-L1 expression • TP53 mutation • KRAS mutation • KRAS G12C • EGFR L858R • KRAS G12D • KRAS G12V • STK11 mutation • KRAS G12A • KRAS G12 • KRAS G13 • KRAS G13C • KRAS V12

9ms

Clinical Impact of Next-Generation Sequencing in KRAS-Mutated Non-Small Cell Lung Cancer Patients: a Single-Center Experience (IASLC-WCLC 2023)

The clinicopathological characteristics of included patients were consistent with the published literature. In the majority of KRAS-mutated patients included in this study, the use of NGS allowed for the detection of additional genetic alterations with potential clinical significance.

9 months ago

Clinical • Next-generation sequencing • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)

KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12 • KRAS G12S • KRAS G13 • KRAS G13C

9ms

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.

9 months ago

Clinical • Real-world evidence • PD(L)-1 Biomarker • IO biomarker • Real-world • Metastases

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)

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

9ms

Molecular Characterization of Non-small Cell Lung Cancer in People Living with HIV or Solid Organ Transplants (IASLC-WCLC 2023)

The identification of targetable genomic alterations in tumors from individuals living with HIV and solid organ transplant recipients underscores the importance of comprehensive molecular testing in these patient populations. While important markers of immunotherapy response (PD-L1, TMB) were similar, different immune characteristics were identified. Further research is necessary to fully understand the molecular profiles of lung cancer in individuals with HIV and solid organ transplant.

9 months ago

Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • 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) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • LAG3 (Lymphocyte Activating 3) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • KDM5C (Lysine Demethylase 5C)

PD-L1 expression • TP53 mutation • KRAS mutation • TMB-H • KRAS G12C • NRAS mutation • PIK3CA mutation • HER-2 mutation • KRAS G12D • PTEN mutation • KRAS G12V • MET exon 14 mutation • STK11 mutation • KRAS G12 • KRAS G13 • NRAS G12D • LAG3 expression • NRAS G13 • KRAS G13C

PD-L1 IHC 22C3 pharmDx • MI Tumor Seek™

over1year

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

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

over 1 year ago

Review • Journal

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

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

almost2years

Clinical characteristic and outcomes of KRAS G13 mutant non-small cell lung cancers. (ASCO 2022)

Pts with KRAS G13C/D had poor survival and response to therapies in comparison with G12C and other non-G12C KRAS mts, particularly with IO-containing regimens. Recently (Judd et al, MCT-21-0201), STK11 and KEAP1 were reported to be frequently co-mutated with KRAS G13* (37.3 and 12.6%) compared to other KRAS mts, and this genotypemay confer primary resistance to IO. We hypothesize that the poor outcomes and immune resistance in G13* mut may be secondary to higher prevalence of STK11 and KEAP1 co-mutations.

almost 2 years ago

Clinical • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)

KRAS mutation • KRAS G12C • STK11 mutation • KEAP1 mutation • KRAS G12 • KRAS G13 • KRAS G13C

2years

Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design. (PubMed, Expert Opin Drug Discov)

Despite the efforts of more than four decades, not many KRAS inhibitors have been successful in obtaining clinical approval, except the very recent FDA approval for sotorasib...In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.

2 years ago

Journal

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12C • KRAS G12V • KRAS G12 • KRAS G13 • KRAS G13C

Lumakras (sotorasib)

2years

KRAS G12C lung adenocarcinoma represents a distinct group of patients with different response to immunotherapy (ELCC 2022)

Additional biomarkers might be helpful in selecting the best therapy for patients harboring KRAS G12C mutations. Legal entity responsible for the study The authors.

2 years ago

Clinical • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)

PD-L1 expression • KRAS mutation • KRAS G12C • KRAS G12V • PD-L1 negative • KRAS G12A • KRAS G12 • KRAS G13 • KRAS G13C • KRAS expression

over2years

Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations. (PubMed, Eur J Cancer)

Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.

over 2 years ago

Retrospective data • Journal

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12C • KRAS G13 • KRAS G13C

over2years

[VIRTUAL] Spectrum of Resistance Mechanisms to First, Second and Third Generation Tyrosine Kinase Inhibitors in EGFR Mutant NSCLC Patients (IASLC-WCLC 2021)

Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K Conclusion Resistance development is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

over 2 years ago

Clinical

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) • MET (MET proto-oncogene, receptor tyrosine kinase) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)

TP53 mutation • KRAS mutation • EGFR mutation • KRAS G12C • BRAF mutation • PIK3CA mutation • EGFR L858R • EGFR exon 19 deletion • MET amplification • EGFR T790M • EGFR amplification • EGFR exon 20 insertion • PIK3CA H1047R • KRAS G12V • EGFR C797S • EGFR exon 19 mutation • MET mutation • EGFR exon 19 deletion + EGFR T790M • KRAS G12 • PIK3CA E542K • ALK translocation • EGFR exon 20 mutation • KRAS G13 • BRAF G469A • PIK3CA E542 • KRAS G13C • EGFR H835L • EGFR L833V • PIK3CA exon 9 mutation + HR positive • EGFR E709A • TP53 R213

Oncomine Focus Assay

almost3years

[VIRTUAL] Primary and secondary resistance mechanisms in first, second and third generation tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer patients. (ASCO 2021)

Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs . NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

almost 3 years ago

Clinical

TP53 mutation • KRAS mutation • EGFR mutation • KRAS G12C • BRAF mutation • PIK3CA mutation • EGFR L858R • EGFR exon 19 deletion • MET amplification • EGFR T790M • EGFR amplification • EGFR exon 20 insertion • PIK3CA H1047R • KRAS G12V • EGFR C797S • EGFR exon 19 mutation • MET mutation • EGFR exon 19 deletion + EGFR T790M • KRAS G12 • PIK3CA E542K • ALK translocation • EGFR exon 20 mutation • KRAS G13 • BRAF G469A • PIK3CA E542 • KRAS G13C • PIK3CA exon 9 mutation + HR positive • EGFR E709A • TP53 R213

Oncomine Focus Assay

3years

[VIRTUAL] Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models (AACR 2021)

Collectively, these data demonstrate that voruciclib inhibition of CDK9 leads to reduced phosphorylation of MYC on Ser 62 followed by a decrease in total MYC protein in MIA PACA-2 cells and inhibition of growth in multiple KRAS mutant cancer cell lines in vivo and in vitro. This suggests that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC.

3 years ago

Preclinical

KRAS (KRAS proto-oncogene GTPase) • CDK9 (Cyclin Dependent Kinase 9)

KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G13D • KRAS G12A • KRAS G12 • KRAS G12S • KRAS G13 • KRAS Q61H • MCL1 expression • KRAS Q61 • KRAS G13C

voruciclib (ME-522)

over3years

[VIRTUAL] Different Types of CDK4 Mutations in East Asian Non-Small Cell Lung Cancer Patients (IASLC-WCLC 2020)

Next generation sequencing showed that CDK4 mutations commonly co-existed with other driver genes. Our results show that CDK4 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through CDK4 inhibitior palbociclib might offer new opportunities.

over 3 years ago

Clinical

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4)

TP53 mutation • EGFR mutation • ALK mutation • KRAS G13C • CDK4 mutation

Ibrance (palbociclib)

over3years

[VIRTUAL] Prevalence, Clinical Characteristics and Survival of Patients with KRAS Mutant Lung Cancer in Argentina. (IASLC-WCLC 2020)

This is similar to previously reported data in other western countries, and higher than reported in overall in Latin America. Extensive molecular profiling of lung cancer can identify potentially targetable KRAS G12C mutations and help to select a subgroup of patients that can benefit with clinical trials targeting KRAS.

over 3 years ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12A • KRAS G12S • KRAS Q61H • KRAS G13C

almost4years

Brief report: efficacy of immune checkpoint inhibitors in KRAS-mutant Non-small cell lung cancer (NSCLC). (PubMed, J Thorac Oncol)

For patients with KRASm NSCLC (all mutational subtypes), the efficacy of ICI is similar to that of patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICI in KRASm NSCLC than it is in other types of NSCLC.

almost 4 years ago

Clinical • Retrospective data • Journal • Checkpoint inhibition • PD(L)-1 Biomarker

KRAS (KRAS proto-oncogene GTPase)

PD-L1 expression • KRAS mutation • PD-L1 overexpression • KRAS G12C • KRAS G12V • KRAS G12A • KRAS G12 • KRAS G13 • KRAS G13C • KRAS expression

almost4years

[VIRTUAL] Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with BRAF V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC). (ASCO 2020)

P2 | "57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings."

almost 4 years ago

P2 data • Clinical

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • JAK3 (Janus Kinase 3)

BRAF V600E • KRAS mutation • BRAF V600 • KRAS G12V • MET exon 14 mutation • ALK fusion • KRAS G12 • KRAS G13 • KRAS G13C

Oncomine™ Dx Target Test

Mekinist (trametinib) • Tafinlar (dabrafenib)