ArticleBMC cancer2022
An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.
Article in BMC cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed.
- Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis.eLife · 2026Article
- Targeting Pyruvate Kinase M2: Signal Transduction Pathways and Exploration of Cancer Therapeutic Strategies.The AAPS journal · 2026Review
- Multiparametric magnetic resonance imaging-based predictive model for chemotherapy response in colorectal cancer patients with gene mutations.World journal of gastrointestinal oncology · 2025Article
- Progastrin Promotes Colorectal Cancer Stem Cell-Like Properties via the Receptor PZR.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Collagen disorder architecture features are associated with clinical, molecular, genetic factors and survival outcomes in colon cancer.NPJ precision oncology · 2025Article
- Identifying distinct prognostic and predictive contributions of tumor epithelium versus tumor microenvironment in colorectal cancer.BMC cancer · 2025Article
- Article
- Anti-Cancer and Pro-Immune Effects of Lauric Acid on Colorectal Cancer Cells.International journal of molecular sciences · 2025Article
- Multi-omics integration and machine learning-driven construction of an immunogenic cell death prognostic model for colon cancer and functional validation of FCGR2A.Frontiers in pharmacology · 2025Article
- Autofluorescent Cancer Stem Cells: Potential Biomarker to Predict Recurrence in Resected Colorectal Tumors.Cancer research communications · 2024Article
- Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- Scalable integration of multiomic single-cell data using generative adversarial networks.Bioinformatics (Oxford, England) · 2024Article
- An integrated model for predicting KRAS dependency.PLoS computational biology · 2023Article
- Propofol enhances stem-like properties of glioma via GABAStem cell research & therapy · 2022Article
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10 authors.
Funding
Abstract
backgroundOver half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s).
methodsWe classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi "bypass" resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154).
resultsHere we report a central role of SRC in mediating "bypass"-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10
conclusionsLarge human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node--an Achilles' heel--in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.
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