IGF1R

IGF1R (Insulin-like growth factor 1 receptor)

一行要約

IGF1R (15q26.3、HGNC:5465) は insulin receptor family の RTK で、IGF-1 / IGF-2 を ligand として heterotetrameric (α2β2) 受容体形成 → IRS-1/2 → PI3K-AKT / MAPK signaling を駆動する。SCLC・乳癌・神経内分泌腫瘍・ユーイング肉腫で高発現し、survival / proliferation / EMT を促進。SCLC では ASCL1-IGFBP5-IGF1R 軸が”血液腫瘍関門様 vascular gate (BVG)“を能動的に組み立てて T 細胞を物理的に排除することが Wang ら (Wang et al. Cell 2026) で発見され、IGF1R 阻害剤 OSI-906 (linsitinib) + anti-PD-1 が BVG を脱正常化して T 細胞浸潤を回復、強力な抗腫瘍効果を発揮した。BVG signature が IMpower133 で ICI PFS を予測したことが臨床応用の柱。OSI-906 単剤の SCLC Phase II は陰性だったが、ICI 併用 paradigm として復活した代表例。

主要エビデンス

• SCLC BVG paradigm (Wang 2026): 神経内分泌腫瘍 (SCLC・前立腺 NEC・SCNEC of cervix) が BBB に類似した tight junction / 厚い基底膜 / pericyte 被覆を伴う “vascular gate” を腫瘍細胞自身が能動形成。ASCL1 → IGFBP5 → IGF1R signaling が血管壁細胞 (endothelial / pericyte) に対する paracrine cue として作用し、過剰正常化された血管を構築 → CD8+ T 細胞物理排除。OSI-906 (linsitinib) + anti-PD-1 が BVG を脱正常化し T 細胞浸潤を回復、IMpower133 cohort で BVG signature が PFS 予測
• EGFR-TKI 耐性での IGF1R bypass: IGF1R 過剰発現 / activation は EGFR-TKI / KRAS-G12C 阻害剤に対する PI3K-AKT bypass 耐性機構の代表 (Rotow et al. NatRevCancer 2017 系列)
• ユーイング肉腫: EWS-FLI1 driven な IGF-1 autocrine が IGF1R inhibitor (ganitumab / figitumumab) の早期成功の rationale だったが、Phase III で OS benefit 証明できず開発中断
• Lineage plasticity・EMT 駆動: IGF1R activation は SCLC NE → non-NE / EMT-like transformation の driver の一つ。EGFR-mutant NSCLC の SCLC transformation でも IGF1R signaling 活性化が報告

メカニズム

• 構造 / activation: IGF-1 / IGF-2 が α subunit に結合 → β subunit kinase domain の trans-autophosphorylation → IRS-1/2 docking
• 下流 signaling:
• PI3K-AKT-mTOR: survival / proliferation / protein synthesis
• MAPK-ERK: proliferation / migration
• SHC-Grb2-SOS-RAS: alternative MAPK activation
• Insulin receptor (INSR) との hybrid receptor: IGF1R-INSR heterodimer が組織別比率で形成、IGF-1/2 と insulin の cross-binding で signaling crosstalk
• IGFBP family による調節: IGFBP1-7 が circulating / local IGF-1 を sequester。IGFBP5 は ASCL1 直接 target で SCLC で過剰発現 → 局所 IGF-1 を腫瘍周囲血管壁に供給
• SCLC BVG での独自経路: ASCL1 (master TF) → IGFBP5 (paracrine carrier) → IGF1R (endothelial / pericyte) → tight junction protein / basement membrane component の transcriptional upregulation → vascular hyperstabilization → T 細胞排除

臨床位置づけ

• OSI-906 (linsitinib) の復活: SCLC Phase II 単剤陰性 (NCT01533181) → BVG paradigm 発見で ICI 併用 partner として再評価。Wang 2026 の前臨床データを受けて Phase 1/2 臨床試験設計の議論段階
• NSCLC EGFR-TKI 耐性 bypass: 耐性メカニズムとして IGF1R 単独阻害は efficacy 限定的、AXL / MET / HER3 と並ぶ multi-RTK targeting の一翼
• 副作用: IGF1R-INSR cross-inhibition による hyperglycemia が dose-limiting toxicity (monoclonal antibody dalotuzumab / cixutumumab / figitumumab で頻発)
• BVG signature の predictive biomarker 開発: IMpower133 で BVG signature が ICI PFS 予測 → SCLC ICI 患者選択 marker 候補

Open Questions

• BVG paradigm の他 NE 腫瘍への展開: 前立腺 NEC / 神経内分泌腫瘍 (NET)・甲状腺髄様癌・カルチノイドで BVG が形成されるか
• OSI-906 + anti-PD-(L)1 の臨床用量・スケジュール: hyperglycemia 管理と T 細胞浸潤 timing
• ASCL1 → IGFBP5 → IGF1R 軸の epigenetic 制御: NE-non-NE transition で BVG が dynamic に変動するか
• CNS active な OSI-906: SCLC 脳転移での BVG 制御と IGF1R inhibitor の脳内分布
• IGF-1 autocrine vs paracrine の relative contribution: 腫瘍細胞自身 vs 血管壁 IGF1R signaling のどちらが律速か
• Pan-NE biomarker としての IGFBP5 IHC: 病理診断への組み込み

関連エンティティ

• 関連経路: PI3K-AKT-mTOR-pathway / MAPK-RAS-ERK-pathway / VEGF-angiogenesis-pathway / BBB-neurovascular-unit-pathway
• 関連遺伝子: ASCL1 / NEUROD1 / POU2F3 / EGFR / MYC
• 関連細胞種: Endothelial-cell / Pericyte / Tumor-endothelial-cell / Neuroendocrine-cell
• 関連概念: SCLC-molecular-subtypes / IO-primary-resistance / Tumor-angiogenesis / Vascular-normalization / Lineage-plasticity / BBB-disruption-in-brain-metastasis

関連論文

直近 30 件のみ表示中 (関連 73 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Satcher et al. NatRevCancer 2022 — Evolving cancer-niche interactions and therapeutic targets during bone metastasis

Basic-Extracellular vesicles

• Guo et al. JExtracellVesicles 2018 — Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles

Basic-Immunotherapy

• Kitajima et al. CancerCell 2018 — Overcoming resistance to dual innate immune and MEK inhibition downstream of KRAS
• McGinnis et al. CancerCell 2024 — The temporal progression of lung immune remodeling during breast cancer metastasis
• Wang et al. Cell 2026 — A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers

Basic-Neutrophil and myeloid cell

• Gao et al. CellMetab 2026 — Restricting lipid accumulation in tumor-infiltrating neutrophils mediates caloric restriction-induced anti-cancer

Basic-Oncogene and genetics

• Huang et al. GenesDev 2018 — POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer
• Mikubo et al. JThoracOncol 2021 — Mechanism of drug tolerant persister cancer cells the landscape and clinical implication for therapy
• Du et al. MolCancer 2018 — Mechanisms of receptor tyrosine kinase activation in cancer
• Zhang et al. Science 2026 — Stem cell control in the lung by an autocrine injury-activated igf complex

Basic-Others

• Monroe et al. NatRevDrugDiscov 2026 — Therapeutic targeting of neuroimmune mechanisms in neurodegeneration

Basic-Tumor microenvironment

• Remsing et al. SciSignal 2022 — IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung

Clinical-NEC

• Lantuejoul et al. TranslLungCancerRes 2020 — New molecular classification of large cell neuroendocrine carcinoma and small cell lung carcinoma with potential

Clinical-NSCLC-ALK

• Fukuda et al. CancerRes 2019 — Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK
• Katayama et al. CancerSci 2018 — Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer
• Dagogo-Jack et al. ClinCancerRes 2020 — MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer
• Naito et al. JpnJClinOncol 2021 — Brigatinib and lorlatinib their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous
• Trigg et al. NatCommun 2019 — The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status
• Dardaei et al. NatMed 2018 — SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Clinical-NSCLC-Driver-Other

• Kim et al. Cell 2020 — Targeting KRAS(G12C) from inhibitory mechanism to modulation of antitumor effects in patients

Clinical-NSCLC-EGFR

• Ricordel et al. AnnOncol 2018 — Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer
• Westover et al. AnnOncol 2018 — Mechanisms of acquired resistance to first-and second-generation EGFR tyrosine kinase inhibitors
• Tanaka et al. CancerCell 2021 — Targeting aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM-and
• Kumagai et al. NatRevCancer 2021 — Antitumour immunity regulated by aberrant ERBB family signalling
• Asao et al. RespirInvestig 2019 — Resistance to molecularly targeted therapy in non-small-cell lung cancer

Clinical-Novel modalities

• Baker et al. Cell 2026 — AI-driven discovery of GPNMB CAR T cells as a multi-cancer therapy
• Zhou et al. CellRepPhysSci 2025 — Challenges and opportunities for lysosome-targeting chimeras

Clinical-SCLC

• Rudin et al. NatRevCancer 2019 — Molecular subtypes of small cell lung cancer a synthesis of human and mouse model data
• Rudin et al. NatRevDisPrimers 2021 — Small-cell lung cancer

Clinical-Thymic

• Prays et al. SeminDiagnPathol 2022 — Molecular landscape of thymic epithelial tumors