News - KRAS G12D + KRAS G12V

Site-Specific Mutagenesis Screening in KRASG12D Mutant Library to Uncover Resistance Mechanisms to KRASG12D Inhibitors. (PubMed, Cancer Lett)

We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

5 days ago

Journal

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12D • KRAS G12D + KRAS G12V • KRAS Q99L

MRTX1133

24d

Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations. (PubMed, Molecules)

The discovered noncovalent KRASG12D inhibitors exhibit promises as potential candidates for targeted therapy against KRASG12D-driven cancers. This comprehensive computational framework not only expedites the discovery of novel KRASG12D inhibitors but also provides valuable insights for the development of precision treatments tailored to this oncogenic mutation.

24 days ago

Journal

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation • KRAS G12D • KRAS G12D + KRAS G12V

12ms

Not all treated KRAS-mutant pancreatic adenocarcinomas are equal: KRAS G12D and survival outcome. (ASCO 2023)

Patients with G12D mutations have significantly lower survival compared to G12R. Significant molecular differences were seen in MAPK pathway gene expression, markers of immune activation, and genes involved in glucose and glutamine metabolism. Intriguingly, metformin use appeared to impact survival in the KRAS G12R subgroup.

12 months ago

PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • KMT2D (Lysine Methyltransferase 2D) • SMAD4 (SMAD family member 4)

PD-L1 expression • TP53 mutation • KRAS mutation • TMB-H • MSI-H/dMMR • KRAS G12C • KRAS G12D • ARID1A mutation • KRAS G12V • KRAS G12R • CDKN2A mutation • KMT2D mutation • KRAS G12 • SMAD4 mutation • KRAS G12D + KRAS G12V

metformin

1year

MODELING FUNCTIONAL HETEROGENEITY USING BRANCHED PANCREATIC CANCER-DERIVED ORGANOIDS REVEALS CONTRACTILE PHENOTYPES INDEPENDENT OF DRIVER MUTATION (DDW 2023)

In summary, our data suggests that distinct organoid phenotypes demonstrate pronounced functional differences – in this case contractility - across different driver mutations. Our contractility readout revealed significant functional heterogeneity regarding different organoid phenotypes which might be an indicator for distinct biological properties involved in the metastatic cascade and might facilitate developing migrastatic treatments in PDAC patients in the future.

1 year ago

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A)

KRAS G12D • CDKN2A mutation • KRAS G12 • KRAS G12D + KRAS G12V

over1year

Use of DNA-alkylating pyrrole-imidazole polyamides for anti-cancer drug sensitivity screening in pancreatic ductal adenocarcinoma. (PubMed, Cancer Med)

These data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.

over 1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • RAD51 (RAD51 Homolog A)

KRAS mutation • KRAS G12D • KRAS G12 • KRAS G12D + KRAS G12V • RAD51 mutation

almost2years

Targetable Alterations in Non-Small Cell Lung Cancer According to Age and Sex (IASLC-WCLC 2022)

Our study demonstrated differences in the distribution of targetable genomic alterations according to age and sex. While these alterations tend to occur in isolation, some co-exist. These findings will likely help individualize treatment and improve outcomes in patients with NSCLC.

almost 2 years ago

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • STK11 (Serine/threonine kinase 11) • NTRK (Neurotrophic receptor tyrosine kinase)

KRAS G12C • HER-2 amplification • EGFR L858R • EGFR exon 19 deletion • MET amplification • EGFR T790M • KRAS G12D • EGFR exon 20 insertion • KRAS G12V • MET exon 14 mutation • EGFR L861Q • EGFR G719X • EGFR S768I • KRAS G12 • EGFR exon 20 mutation • KRAS G12D + KRAS G12V • EGFR L858R + EGFR S768I

Guardant360® CDx

over2years

SLC25A22 drives immune suppression in kras-mutant colorectal cancer (IDDF 2021)

SLC25A22 recruits MDSC migration via CXCL1/CXCR2 axis, IDDF2021-ABS-0183 Figure 6. SLC25A22 recruits MDSC migration via CXCL1/CXCR2 axis) Conclusions Our work suggests a SLC25A22-chemokine axis that promotes an immune suppressive microenvironment in KRAS-mutant CRC and implies that SLC25A22 constitutes a novel target for immunotherapies.

over 2 years ago

IO biomarker

KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • CXCR2 (Chemokine (C-X-C motif) receptor 2) • CXCL1 (Chemokine (C-X-C motif) ligand 1) • CXCL3 (C-X-C Motif Chemokine Ligand 3)

KRAS mutation • KRAS G12D • KRAS G12 • KRAS G12D + KRAS G12V

almost3years

[VIRTUAL] Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC). (ASCO 2021)

The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice . In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease . This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

almost 3 years ago

Clinical

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • HRD (Homologous Recombination Deficiency) • NRG1 (Neuregulin 1) • CDK4 (Cyclin-dependent kinase 4) • NTRK (Neurotrophic receptor tyrosine kinase)

KRAS mutation • KRAS G12C • KRAS G12D • HRD • KRAS G12V • NRG1 fusion • KRAS G12 • CDK4 amplification • KRAS G12D + KRAS G12V • BRAF amplification

gemcitabine • albumin-bound paclitaxel

3years

[VIRTUAL] Colorectal NECs and MANECs: A monocenter pilot retrospective analysis (ENETS 2021)

The mutational pattern analysis suggested that crNECs and crMANECs undergo specific cancerogenic pathways to be explored in future prospective studies.

3 years ago

Retrospective data • BRCA Biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • NOTCH1 (Notch 1) • ATRX (ATRX Chromatin Remodeler) • TSC2 (TSC complex subunit 2) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • CCND3 (Cyclin D3)

TP53 mutation • KRAS G12D • KRAS G13D • KRAS G12 • KRAS G13 • TSC2 mutation • KRAS A146T • KRAS G12D + KRAS G12V • TP53 R273H