ArticleJournal of experimental & clinical cancer research : CR2019
Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression.
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 25 papers.
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Who cites it
25 citing papers in PubMed, 39 citations in OpenAlex.
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- Regulatory mechanisms of PD-1/PD-L1 in cancers.Molecular cancer · 2024Review
- Integrin αvβ6 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon carcinoma.American journal of cancer research · 2024Article
- Comprehensive characterization of B7 family members in NSCLC and identification of its regulatory network.Scientific reports · 2023Article
- Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer.World journal of gastrointestinal oncology · 2023Article
- Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies.International journal of molecular sciences · 2023Review
- Influence of location-dependent sex difference on PD-L1, MMR/MSI, and EGFR in colorectal carcinogenesis.PloS one · 2023Article
- Identification and verification of a prognostic signature based on a miRNA-mRNA interaction pattern in colon adenocarcinoma.Frontiers in cell and developmental biology · 2023Article
- Circulating lncRNA EGFR-AS1 as a diagnostic biomarker of colorectal cancer and an indicator of tumor burden.Journal of gastrointestinal oncology · 2022Article
- Molecular Pathogenesis of Colorectal Cancer: Impact of Oncogenic Targets Regulated by Tumor SuppressiveInternational journal of molecular sciences · 2022Article
- Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells.Marine drugs · 2022Article
- Review
- Oncopeptide MBOP Encoded byCancers · 2022Article
- Colorectal cancer development is affected by the ECM molecule EMILIN-2 hinging on macrophage polarization via the TLR-4/MyD88 pathway.Journal of experimental & clinical cancer research : CR · 2022Article
- Progress in the Study of Colorectal Cancer Caused by Altered Gut Microbiota After Cholecystectomy.Frontiers in endocrinology · 2022Review
- Emerging Therapeutic Agents for Colorectal Cancer.Molecules (Basel, Switzerland) · 2021Review
- Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?International journal of molecular sciences · 2021Review
- Review
- The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundMolecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance.
methodsWe have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance.
resultsThe three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models.
conclusionsThese results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
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