Lung cancer, intracellular signaling pathways, and preclinical models
type: Dataset
description: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the conséquences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative therapeutics. W…
landing page: https://theses.hal.science/tel-00809668
identifier: NNT: 2012PA11T092
keyword: braf
keyword: cancer-bronchique
keyword: cancer-bronchique-non-a-petites-cellules
keyword: cellules-tumorales-circulantes
keyword: circulating-tumor-cells
keyword: infoeu-reposemanticsdoctoralthesis
keyword: kras
keyword: lung-cancer
keyword: modeles-murins-orthotopiques
keyword: non-small-cell-lung-cancer
keyword: orthotopic-animal-models
keyword: pik3
keyword: sdvcanlife-sciences-q-biocancer
keyword: targeted-therapies
keyword: therapies-ciblees
keyword: theses
issued: 2026-05-11T12:18:43.201868
modified: 2026-05-11T12:18:43.201873
language: fr
contact point: Organization
  fn: CCSD

test_moissonnage_selune
type: Agent

Lung cancer, intracellular signaling pathways, and preclinical models
type: Distribution
format: HTML
access URL: https://theses.hal.science/tel-00809668
issued: 2026-05-11T12:18:43.219024
modified: 2026-05-11T12:18:43.174801