ArticleJournal of experimental & clinical cancer research : CR2019
Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 89 citations in OpenAlex.
- Targeting MAPK Pathways in Skin, Thyroid, and Pancreatic Cancer: A Perspective on Synthetic Inhibitors and Natural Modulators.Advanced biology · 2026Review
- KRAS in Colorectal Cancer: Tumorigenesis, Surgical Implications and Evolving Treatment Target.Current oncology (Toronto, Ont.) · 2026Review
- Capmatinib and paclitaxel combination: a novel strategy for overcoming challenges in triple-negative breast cancer treatment.BMC cancer · 2026Article
- Targeting cell death: a promising approach for colorectal cancer therapy.Cancer cell international · 2026Review
- Colorectal cancer pathogenesis, oncogenic signaling networks and targeted therapeutic advances.Molecular biomedicine · 2026Review
- AI-enabled multi-omics integration in colorectal cancer: from molecular stratification to clinical translation.Frontiers in cell and developmental biology · 2026Review
- Gene Mutations and Related Molecular Events in Distant Metastasis of Cervical Cancer: A Review.International journal of medical sciences · 2026Review
- Bispecific antibody-drug conjugates: a modular blueprint for next-generation cancer therapeutics.Archives of pharmacal research · 2026Review
- The cost-effectiveness analysis of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair deficient advanced colorectal cancer.Scientific reports · 2025Article
- Differential Response and Resistance to KRAS-Targeted Therapy.Molecular carcinogenesis · 2025Review
- KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.Cell reports · 2025Article
- Targeting NUCKS1 with a fragment of tRNANon-coding RNA research · 2025Article
- Biomarkers for colorectal cancer detection: An insight into colorectal cancer and FDA-approved biomarkers.BioImpacts : BI · 2025Review
- Pan-Immune-Inflammation Value (PIV) and Prognostic Nutritional Index (PNI) are Associated with Distant Metastasis in Colorectal Cancer withInternational journal of general medicine · 2025Article
- Advances in the diagnosis of colorectal cancer: the application of molecular biomarkers and imaging techniques: a literature review.Annals of medicine and surgery (2012) · 2025Review
- Precision medicine in colorectal cancer: genomics profiling and targeted treatment.Frontiers in pharmacology · 2025Review
- Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.Science translational medicine · 2024Article
- Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance.International journal of molecular sciences · 2024Review
- [High expression of fragile X mental retardation protein inhibits ferroptosis of colorectal tumor cells by activating the RAS/MAPK signaling pathway].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2024Article
- Cell-Permeable Fluorescent Sensors Enable Rapid Live Cell Visualization of Plasma Membrane and Nuclear PIP3 Pools.JACS Au · 2024Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundPrevious studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC.
methodsWe generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones.
resultsWe found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors.
conclusionsPI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.
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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.