NTRK

NTRK (NTRK1 / NTRK2 / NTRK3)

一行要約

NTRK1/2/3 (TRKA/B/C) は神経成長因子受容体ファミリーで、活性化 fusion は tissue-agnostic driver として infantile fibrosarcoma / secretory carcinoma / MASC (>90%) から NSCLC (<1%) / CRC (約0.5%) / GBM まで横断的に出現する。Larotrectinib (Drilon et al. NEnglJMed 2018、Hong et al. LancetOncol 2020) と Entrectinib (Doebele et al. LancetOncol 2020) が pan-cancer NTRK fusion で承認された tissue-agnostic targeted therapy paradigm の代表例で、NSCLC NTRK1 rearrangement の oncogenic / drug-sensitive nature を Vaishnavi et al. NatMed 2013 が初めて示した。耐性は solvent-front G595R (NTRK1) / G623R (NTRK3) と gatekeeper F589L が中心で、Repotrectinib (Drilon et al. NEnglJMed 2024 TRIDENT-1) が次世代として開発された。

メカニズム

NTRK1 / 2 / 3 は通常神経系で発現する RTK で:

• リガンド: NGF (NTRK1), BDNF / NT-4 (NTRK2), NT-3 (NTRK3)
• 二量体化 → autophosphorylation → RAS-MAPK / PI3K-AKT / PLCγ activation
• 通常成体では神経系限定発現
• RTK signaling general principle は Lemmon et al. Cell 2010 / Du et al. MolCancer 2018 が網羅的に整理

Activating fusion:

• 5’ partner (TPM3, ETV6, LMNA, TFG, SQSTM1 等) の二量体化ドメインが N 末端に結合
• Constitutive dimerization → 恒常活性化
• Pan-cancer kinase fusion landscape は Stransky et al. NatCommun 2014 が TCGA で systematically map し、NTRK fusion の cross-tumor 分布を提示
• NSCLC で oncogene fusion が exclusive driver になる lineage は Saito et al. CancerRes 2015 が示した

NSCLC NTRK fusion variants:

• NTRK1: TPM3-NTRK1, IRF2BP2-NTRK1, MPRIP-NTRK1 (Vaishnavi et al. NatMed 2013 が初記載)
• NTRK2: rare in NSCLC
• NTRK3: ETV6-NTRK3, EML4-NTRK3

Resistance:

• NTRK1 G595R (solvent-front, cross-resistant、ALK G1202R / ROS1 G2032R 相当)
• NTRK1 F589L (gatekeeper)
• NTRK3 G623R (solvent-front)
• 機構整理: Fuse et al. MolCancerTher 2017 が NTRK1-rearranged cancer の 1st-gen TKI 耐性 mutation スペクトラムと next-gen 戦略をまとめた reference

主要エビデンス

Pan-cancer pivotal

• Larotrectinib (pan-cancer selective NTRK inhibitor) : Drilon et al. NEnglJMed 2018 が小児 / 成人 17 cancer types pooled で ORR 75% を報告、初の tissue-agnostic FDA 承認 (2018)。pediatric を含む extended cohort は Hong et al. LancetOncol 2020、adult phase I dose-escalation は Hong et al. AnnOncol 2019、別 cohort は Schrock et al. AnnOncol 2019
• Larotrectinib mechanism: Huang et al. Cell 2019 と Huang et al. Cell 2019 が tumor-agnostic NTRK inhibitor の selectivity / efficacy 基盤を提示
• Index case: Doebele et al. CancerDiscov 2015 が LOXO-101 (larotrectinib) の最初の臨床効果を soft-tissue sarcoma で報告し pan-cancer paradigm のきっかけ

Entrectinib (NTRK / ROS1 / ALK multi-kinase)

• Pan-cancer integrated: Doebele et al. LancetOncol 2020 が STARTRK-1 / STARTRK-2 / ALKA-372-001 統合で ORR 57%、CNS efficacy が最大の差別化 (intracranial ORR 55%)。同 cohort 別解析: Doebele et al. LancetOncol 2020
• Phase I early: Drilon et al. CancerDiscov 2017 / Drilon et al. CancerDiscov 2017 が ALKA-372-001 / STARTRK-1 で initial activity を報告
• NSCLC durable case: Farago et al. JThoracOncol 2015 が NSCLC NTRK-positive で長期 PFS 症例
• Asian cohort: Doebele et al. LancetOncol 2020 が Asian で Entrectinib の efficacy / safety を確認
• Discovery / PK: Menichincheri et al. JMedChem 2016 が entrectinib 創薬、Ardini et al. MolCancerTher 2016 が pan-target activity profiling、Parrott et al. AAPSJ 2020 が food / pH effect の PBPK modeling

次世代 NTRK-TKI (耐性克服)

• Repotrectinib: Drilon et al. NEnglJMed 2024 TRIDENT-1 が ROS1 fusion-positive NSCLC で pivotal、NTRK arm も含む macrocyclic next-gen TKI で solvent-front G595R / G2032R 克服を企図
• DS-6051b (taletrectinib) : Katayama et al. NatCommun 2019 が DS-6051b の ROS1 / NTRK selective で G2032R 克服を preclinical 実証

Diagnostic / detection

• Solomon et al. CancerRes 2019 が IHC / FISH / RNA-seq / DNA-NGS の検出感度を比較、pan-TRK IHC は NTRK1/2 で sensitive だが NTRK3 で false-negative リスク → RNA-based assay 推奨
• NSCLC plasma genotyping は Aggarwal et al. NatRevClinOncol 2021 が ctDNA NTRK fusion 検出戦略を整理
• Comprehensive cfDNA: Leighl et al. ClinCancerRes 2019 が metastatic NSCLC 初診で NTRK 含む rare fusion の cfDNA 同定 utility
• NEC / LCNEC: Heijboer et al. JCOPrecisOncol 2025 が LCNEC で NTRK 含む actionable alteration の treatable case を報告

Reviews / contextualization

• Cocco et al. NatRevClinOncol 2018 が NTRK fusion / TRK inhibitor の総説 reference
• Vaishnavi et al. CancerDiscov 2015 が NTRK の歴史的経緯を編集
• Resistance mechanism overview: Rotow et al. NatRevCancer 2017、Katayama et al. CancerSci 2018 が ALK / ROS1 / NTRK で共通する solvent-front / gatekeeper paradigm を提示
• ALK / EGFR との fusion crosstalk: Vaishnavi et al. CancerRes 2017 が fusion kinase 阻害下で EGFR feedback signaling が response を modulate することを示した

Open Questions

• NSCLC NTRK fusion screening: NGS 必須化、IHC スクリーニングの sensitivity (特に NTRK3 で false-negative、Solomon et al. CancerRes 2019 が指摘) → RNA-based assay or DNA fusion panel の併用
• G595R 後 4th-gen NTRK-TKI: Selitrectinib (LOXO-195) の clinical move、Repotrectinib の post-larotrectinib efficacy (Drilon et al. NEnglJMed 2024 cohort 拡張)
• Adjuvant NTRK-TKI: 切除可能 NTRK fusion+ NSCLC への adjuvant 試験デザイン (NTRK fusion 頻度低く RCT 困難 → registry-based / single-arm pivotal)
• CNS effect: Larotrectinib / Entrectinib / Repotrectinib の BBB 透過性比較、脳転移自然歴の差 (Boire et al. NatRevCancer 2020 / Boire et al. NatRevCancer 2020 の脳転移 framework に rare driver を統合)
• EGFR-mutant 耐性 NTRK fusion: Osimertinib 耐性 mechanism として NTRK fusion が稀に出現 — combination strategy (osimertinib + larotrectinib triplet) の臨床的妥当性

重要論文 Top 10

1. ★★★★★ Drilon et al. NEnglJMed 2018 — Larotrectinib pan-cancer pivotal、初 tissue-agnostic FDA 承認
2. ★★★★★ Doebele et al. LancetOncol 2020 — Entrectinib pooled、CNS efficacy で差別化
3. ★★★★★ Vaishnavi et al. NatMed 2013 — NSCLC NTRK1 fusion の oncogenic / drug-sensitive nature を初記載
4. ★★★★ Drilon et al. NEnglJMed 2024 — TRIDENT-1 (ROS1 cohort、NTRK arm 含む) — solvent-front 克服
5. ★★★★ Cocco et al. NatRevClinOncol 2018 — NTRK fusion / TRK inhibitor 総説 reference

関連エンティティ

• 関連 class: NTRK-inhibitor (Larotrectinib / Entrectinib / Repotrectinib)
• 関連遺伝子: ROS1 (kinase domain 同一性), ALK
• ドメイン: lung-cancer-biology, lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 84 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Chafe et al. SciSignal 2026 — Emerging paradigms in the study of brain metastases

Basic-Liquid-biopsy

• Zhang et al. BrJCancer 2022 — Utility of cell-free DNA from bronchial washing fluid in diagnosis and genomic determination for radiology-suspected
• Samol et al. JCOPrecisOncol 2025 — Prospective multicenter study evaluating a combined circulating tumor DNA and circulating tumor RNA liquid biopsy in
• Jee et al. NatMed 2022 — Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer
• Aggarwal et al. NatRevClinOncol 2021 — Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice

Basic-Neutrophil and myeloid cell

• Tang et al. SciAdv 2022 — Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

Basic-Oncogene and genetics

• Bandlamudi et al. CancerCell 2026 — Cancer type-specific variation in patterns of driver alterations across 50,000 tumors
• Sill et al. CancerCell 2026 — Advancing CNS tumor diagnostics with expanded DNA methylation-based classification
• Myer et al. CancerDiscov 2022 — The genomics of colorectal cancer in populations with African and European ancestry

Basic-Others

• Osarogiagbon et al. AmSocClinOncolEducBook 2026 — Optimal use of targeted therapy and immunotherapy in early-stage, resectable non-small cell lung cancer
• Jimenez-Castano et al. NatCancer 2026 — Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity

Basic-Tumor microenvironment

• Sun et al. DevCell 2022 — A census of the lung CellCards from LungMAP

Clinical-Epidemiology

• Thai et al. Lancet 2021 — Lung Cancer

Clinical-Methodology

• Spreafico et al. CancerDiscov 2021 — The future of clinical trial design in oncology

Clinical-NEC

• Nicholson et al. JThoracOncol 2022 — The 2021 WHO classification of lung tumors impact of advances since 2015
• Nassar et al. NatCommun 2025 — Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Clinical-NSCLC-Driver negative

• Li et al. FrontImmunol 2026 — The application and challenges of immune checkpoint inhibitors in lung cancer therapy
• Xiong et al. Lancet 2026 — Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer
• Wang et al. NatMed 2021 — Toward personalized treatment approaches for non-small-cell lung cancer

Clinical-NSCLC-Driver-Other

• Liu et al. CancerDrugResist 2020 — RET kinase alterations in targeted cancer therapy
• Kropf-Sanchen et al. ClinLungCancer 2026 — A retrospective, multicenter analysis within the national network genomic medicine lung cancer in germany to detect RET

Clinical-NSCLC-EGFR

• Kim et al. FrontOncol 2026 — Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC
• Shields et al. JThoracOncol 2021 — Selpercatinib overcomes CCDC6-RET-mediated resistance to osimertinib

Clinical-NSCLC-ROS1

• Parrott et al. AAPSJ 2020 — Physiologically based absorption modelling to explore the impact of food and gastric pH changes on the pharmacokinetics
• Ma et al. CancerCell 2026 — JYP0322, a highly selective and brain-penetrant ROS1 inhibitor, overcomes ROS1G2032R resistance mutation in NSCLC
• DAngelo et al. Cancers 2020 — Focus on ROS1-positive non-small cell lung cancer (NSCLC) crizotinib, resistance mechanisms and the newer generation of
• Almquist et al. JCOOncolPract 2021 — The road less traveled A guide to metastatic ROS1-rearranged non-small-cell lung cancer
• Ou et al. JTOClinResRep 2021 — Efficacy of taletrectinib (AB-106ds-6051b) in ROS1+ NSCLC an updated pooled analysis of U.S. and japan phase 1 studies
• Drilon et al. NEnglJMed 2024 — Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer

Clinical-Others

• Cowzer et al. ClinCancerRes 2026 — Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer