ArticleMolecular cancer research : MCR2012
KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling.
Article in Molecular cancer research : MCR, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02978547 (The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma), which is not on this map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Effects of Neoadjuvant Metformin on Tumour Cell Proliferation and Tumour Progression in Pancreatic Ductal Adenocarcinoma
Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.Annals of oncology : official journal of the European Society for Medical Oncology · 2015Trial
- Molecular Imaging in Pancreatic Cancer: Current Applications and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies.Clinical and translational medicine · 2026Review
- Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status.Signal transduction and targeted therapy · 2025Review
- Obesity and endocrine-related cancer: The important role of IGF-1.Frontiers in endocrinology · 2023Review
- Remarkable response ofGastroenterology report · 2022Article
- Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Article
- Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes.Small GTPases · 2018Review
- Therapeutic strategies to target RAS-mutant cancers.Nature reviews. Clinical oncology · 2018Review
- Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers.Cell reports · 2017Article
- Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification.Journal of cancer research and clinical oncology · 2016Review
- Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective.World journal of gastroenterology · 2016Review
- Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.Oncogene · 2016Article
- The double trouble of metabolic diseases: the diabetes-cancer link.Molecular biology of the cell · 2015Article
- Article
- Roles for KRAS in pancreatic tumor development and progression.Gastroenterology · 2013Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Mutation of KRAS is a common initiating event in pancreatic ductal adenocarcinoma (PDAC). Yet, the specific roles of KRAS-stimulated signaling pathways in the transformation of pancreatic ductal epithelial cells (PDEC), putative cells of origin for PDAC, remain unclear. Here, we show that KRAS(G12D) and BRAF(V600E) enhance PDEC proliferation and increase survival after exposure to apoptotic stimuli in a manner dependent on MEK/ERK and PI3K/AKT signaling. Interestingly, we find that activation of PI3K/AKT signaling occurs downstream of MAP-ERK kinase (MEK), and is dependent on the autocrine activation of the insulin-like growth factor (IGF) receptor (IGF1R) by IGF2. Importantly, IGF1R inhibition impairs KRAS(G12D)- and BRAF(V600E)-induced survival, whereas ectopic IGF2 expression rescues KRAS(G12D)- and BRAF(V600E)-mediated survival downstream of MEK inhibition. Moreover, we show that KRAS(G12D)- and BRAF(V600E)-induced tumor formation in an orthotopic model requires IGF1R. Interestingly, we show that while individual inhibition of MEK or IGF1R does not sensitize PDAC cells to apoptosis, their concomitant inhibition reduces survival. Our findings identify a novel mechanism of PI3K/AKT activation downstream of activated KRAS, illustrate the importance of MEK/ERK, PI3K/AKT, and IGF1R signaling in pancreatic tumor initiation, and suggest potential therapeutic strategies for this malignancy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.