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<p>Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with a broad clinical spectrum, ranging from indolent localized lesions to aggressive metastatic disease. Approximately half of IMTs harbor oncogenic anaplastic lymphoma kinase (ALK) gene fusions, which drive constitutive kinase activation and render the tumors sensitive to ALK tyrosine kinase inhibitors (ALK-TKIs). Although ALK-targeted therapy has significantly improved outcomes in IMT patients, durable responses are frequently limited by intrinsic and acquired resistance. In this review, we summarize the molecular taxonomy and functional stratification of ALK fusion variants in IMT, highlighting their diagnostic and therapeutic implications. We outline a tiered diagnostic workflow integrating immunohistochemistry, fluorescence in situ hybridization, and RNA-based next-generation sequencing to optimize fusion detection and guide precision treatment selection. We also discuss the major mechanisms of ALK-TKIs resistance—including on-target kinase domain mutations, off-target bypass pathway activation, and lineage plasticity—and propose corresponding clinical countermeasures. Finally, we review emerging therapeutic strategies such as third-generation ALK-TKIs, TRK-sparing brain-penetrant compounds, PROTAC-based degraders, combination regimens, and ctDNA-guided monitoring, aiming to support precision oncology decision-making and improve long-term outcomes for patients with ALK-positive IMT.</p>

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Precision oncology for ALK positive inflammatory myofibroblastic tumor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Yuyu Yang,
  • Zhenzhen Ma

摘要

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with a broad clinical spectrum, ranging from indolent localized lesions to aggressive metastatic disease. Approximately half of IMTs harbor oncogenic anaplastic lymphoma kinase (ALK) gene fusions, which drive constitutive kinase activation and render the tumors sensitive to ALK tyrosine kinase inhibitors (ALK-TKIs). Although ALK-targeted therapy has significantly improved outcomes in IMT patients, durable responses are frequently limited by intrinsic and acquired resistance. In this review, we summarize the molecular taxonomy and functional stratification of ALK fusion variants in IMT, highlighting their diagnostic and therapeutic implications. We outline a tiered diagnostic workflow integrating immunohistochemistry, fluorescence in situ hybridization, and RNA-based next-generation sequencing to optimize fusion detection and guide precision treatment selection. We also discuss the major mechanisms of ALK-TKIs resistance—including on-target kinase domain mutations, off-target bypass pathway activation, and lineage plasticity—and propose corresponding clinical countermeasures. Finally, we review emerging therapeutic strategies such as third-generation ALK-TKIs, TRK-sparing brain-penetrant compounds, PROTAC-based degraders, combination regimens, and ctDNA-guided monitoring, aiming to support precision oncology decision-making and improve long-term outcomes for patients with ALK-positive IMT.