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Background <p>Brain metastases (BrM) from colorectal cancer (CRC) are rare but carry dismal prognosis. Emerging genomic analyses have identified <i>insulin receptor substrate 2</i> (IRS2) amplification as a recurrent event in CRC BrM, suggesting a role in brain tropism and metabolic adaptation.</p> Objective <p>To systematically evaluate clinical, molecular, and preclinical evidence implicating IRS2 in the pathogenesis and therapeutic targeting of CRC brain metastases.</p> Methods <p>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.</p> Results <p>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 <b>7.6% of CRC BrM vs 2.9%</b> of non-brain metastases (<i>p</i> &lt; 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 <b>NT219 + 5-fluorouracil</b> suppressed CRC BrM growth in vivo.</p> Conclusion <p>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.</p>

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IRS2 as a driver and therapeutic target in brain metastases from colorectal cancer: a systematic review of mechanistic and translational evidence

  • 期刊论文

  • 发表日期：

    2026年1月23日

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  • Siddharth Shah,
  • Brandon Lucke-Wold

摘要

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.