IRS2 as a driver and therapeutic target in brain metastases from colorectal cancer: a systematic review of mechanistic and translational evidence.
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[BACKGROUND] Brain metastases (BrM) from colorectal cancer (CRC) are rare but carry dismal prognosis.
- p-value p < 0.0001
APA
Shah S, Lucke-Wold B (2026). IRS2 as a driver and therapeutic target in brain metastases from colorectal cancer: a systematic review of mechanistic and translational evidence.. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. https://doi.org/10.1007/s12094-025-04212-5
MLA
Shah S, et al.. "IRS2 as a driver and therapeutic target in brain metastases from colorectal cancer: a systematic review of mechanistic and translational evidence.." Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 2026.
PMID
41575664 ↗
Abstract 한글 요약
[BACKGROUND] Brain metastases (BrM) from colorectal cancer (CRC) are rare but carry dismal prognosis. Emerging genomic analyses have identified insulin receptor substrate 2 (IRS2) amplification as a recurrent event in CRC BrM, suggesting a role in brain tropism and metabolic adaptation.
[OBJECTIVE] To systematically evaluate clinical, molecular, and preclinical evidence implicating IRS2 in the pathogenesis and therapeutic targeting of CRC brain metastases.
[METHODS] We systematically searched PubMed, Embase, Web of Science, and Scopus (inception-Nov 2025) for studies reporting on IRS2 expression, amplification, or perturbation in CRC with emphasis on brain metastases. Human tissue studies, large genomic datasets, and preclinical models (in vivo/in vitro/ex vivo) were included. Data extraction followed PRISMA 2020 guidelines.
[RESULTS] Among 312 unique records screened, 6 met inclusion criteria (1 large-scale clinical-genomic cohort, 2 preclinical mechanistic studies, 1 therapeutic evaluation, and 2 grey-literature conference reports). The pivotal Neuro-Oncology 2025 study (Greenberg et al.) demonstrated IRS2 amplification in 7.6% of CRC BrM vs 2.9% of non-brain metastases (p < 0.0001) and confirmed protein overexpression by immunohistochemistry. Functional assays revealed that IRS2 overexpression promotes β-catenin activation, oxidative phosphorylation, and CRC survival in brain-like conditions, while silencing reduces intracranial tumor growth and prolongs survival in mice. Treatment with the dual IRS1/2 degrader NT219 + 5-fluorouracil suppressed CRC BrM growth in vivo.
[CONCLUSION] IRS2 amplification represents a recurrent but non-universal molecular alteration enriched in a subset of colorectal cancer brain metastases, with mechanistic links to β-catenin signaling and mitochondrial metabolism. Preclinical inhibition of IRS2/IRS1-2 demonstrates translational promise, positioning IRS2 as a context-dependent vulnerability and potential therapeutic target in selected CRC brain-metastatic tumors.
[OBJECTIVE] To systematically evaluate clinical, molecular, and preclinical evidence implicating IRS2 in the pathogenesis and therapeutic targeting of CRC brain metastases.
[METHODS] We systematically searched PubMed, Embase, Web of Science, and Scopus (inception-Nov 2025) for studies reporting on IRS2 expression, amplification, or perturbation in CRC with emphasis on brain metastases. Human tissue studies, large genomic datasets, and preclinical models (in vivo/in vitro/ex vivo) were included. Data extraction followed PRISMA 2020 guidelines.
[RESULTS] Among 312 unique records screened, 6 met inclusion criteria (1 large-scale clinical-genomic cohort, 2 preclinical mechanistic studies, 1 therapeutic evaluation, and 2 grey-literature conference reports). The pivotal Neuro-Oncology 2025 study (Greenberg et al.) demonstrated IRS2 amplification in 7.6% of CRC BrM vs 2.9% of non-brain metastases (p < 0.0001) and confirmed protein overexpression by immunohistochemistry. Functional assays revealed that IRS2 overexpression promotes β-catenin activation, oxidative phosphorylation, and CRC survival in brain-like conditions, while silencing reduces intracranial tumor growth and prolongs survival in mice. Treatment with the dual IRS1/2 degrader NT219 + 5-fluorouracil suppressed CRC BrM growth in vivo.
[CONCLUSION] IRS2 amplification represents a recurrent but non-universal molecular alteration enriched in a subset of colorectal cancer brain metastases, with mechanistic links to β-catenin signaling and mitochondrial metabolism. Preclinical inhibition of IRS2/IRS1-2 demonstrates translational promise, positioning IRS2 as a context-dependent vulnerability and potential therapeutic target in selected CRC brain-metastatic tumors.
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