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Cooperativity between Ras pathway mutations in colonic tumorigenesis

ABSTRACT: The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC). We previously characterized two activating alleles of KRAS, A59T and A59E, that show impaired BRAF dimerization. These alleles of KRAS are enriched in CRC tumors with genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, NF1). Using a new conditional mouse model of K-Ras (LSL-K-Ras A59E) we show that, despite its inability to universally activate RAF kinases, K-Ras A59E disturbs colon epithelium and decreases mouse survival in a tumor model. By combining LSL-K-Ras A59E mice with a conditional knockout of Nf1, we demonstrate cooperation between these alleles at multiple levels. Consistent with cooperation and clinical observations, we show that K-Ras A59E neither promotes EGF independence of organoid growth, nor confers intrinsic resistance to EGFR inhibition. Thus, our data provide a deeper understanding of the role of RAF isoforms in mutant KRAS driven CRC and argue for the use of anti-EGFR therapies against some Ala59 mutant alleles of KRAS.

ORGANISM(S): Mus musculus

PROVIDER: GSE300614 | GEO | 2025/07/02

REPOSITORIES: GEO

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Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.

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Cooperativity between Ras pathway mutations in colonic tumorigenesis

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