RET

一行要約

Receptor tyrosine kinase。NSCLC では RET fusion (KIF5B-RET 約 70%、CCDC6-RET / NCOA4-RET 等) が 1–2% を占める driver で、若年・非/軽喫煙・腺癌に偏った分布 (Kohno et al. NatMed 2012, Takeuchi et al. NatMed 2012)。MTC (甲状腺髄様癌) では germline / sporadic point mutation (M918T, V804M, C634R) が中心。Selective RET-TKI Selpercatinib / Pralsetinib が multi-kinase 前世代 (vandetanib / cabozantinib / lenvatinib) を機能的・毒性両面で凌駕し、LIBRETTO-431 (Zhou et al. NEnglJMed 2023) で 1L Selpercatinib が pembro + chemo を PFS HR 0.46 で破った。

主要エビデンス

Driver の確立: 2012 年に Kohno et al. NatMed 2012 と Takeuchi et al. NatMed 2012 が KIF5B-RET / CCDC6-RET fusion を独立に同定し、NSCLC 腺癌の 1–2% を占める driver として確立。Pan-cancer kinase fusion landscape は Stransky et al. NatCommun 2014 が体系化。Multi-kinase RET inhibitor (vandetanib / cabozantinib) の早期試験では RET fusion NSCLC で ORR 16–47% にとどまり、off-target VEGFR2 抑制由来の高血圧・proteinuria・hand-foot syndrome が問題となっていた (review: Liu et al. CancerDrugResist 2020, Gainor et al. Oncologist 2013)。

Selective RET-TKI の登場: 構造創薬の breakthrough は Subbiah et al. CancerDiscov 2018 が報告した BLU-667 (pralsetinib 前身) — ATP 結合 site 高選択性で V804 gatekeeper・solvent-front をカバーする design。並行して LOXO-292 (後の selpercatinib) の前臨床根拠を Plenker et al. SciTranslMed 2017 が「inactive conformation drugging」で示した。

Selpercatinib (LIBRETTO-001 → -431) : pivotal phase I/II Drilon et al. NEnglJMed 2020 LIBRETTO-001 で TKI-naive ORR 85% (mPFS NR) / pretreated (platinum 後) ORR 64% / mPFS 16.5 mo / intracranial ORR 91% を提示。1L head-to-head phase III Zhou et al. NEnglJMed 2023 LIBRETTO-431 は selpercatinib vs platinum + pemetrexed ± pembrolizumab で PFS 24.8 vs 11.2 mo (HR 0.46) 、ITT-pembrolizumab 集団でも有意な優位性を示し、RET fusion NSCLC の 1L 標準を確定。CNS PFS も HR 0.28 と CNS active を示した。Selpercatinib の MTC への拡張は Hadoux et al. NEnglJMed 2023 LIBRETTO-531 が cabozantinib / vandetanib に対する優位を示し (LIBRETTO-001 整合)。

EGFR-TKI 耐性 bypass としての RET fusion: Piotrowska et al. CancerDiscov 2018 が 1L Osimertinib 耐性として acquired CCDC6-RET / NCOA4-RET fusion を 約5–10% で同定、Osimertinib + BLU-667 の併用 case で奏効を実証。Mechanism details は Shields et al. JThoracOncol 2021、real-world ドイツ NNGM cohort は Kropf-Sanchen et al. ClinLungCancer 2026 が EGFR-TKI 耐性 RET fusion 検出と臨床的意義を解析。これは EGFR / RET dual-target combination の rational basis。

耐性 mutation - on-target & bypass: vandetanib への activation loop secondary mutation を pre-clinical & 1 例 case で示した Nakaoku et al. NatCommun 2018。selective RET-TKI 耐性として solvent-front G810R/S/C が両 TKI cross-resistant、gatekeeper V804M/L は selective TKI で克服されるが G810 で再発。Bypass は MET amp / KRAS / BRAF 二次変異 / EGFR upregulation。Lung uncommon breakpoint の検出信頼性は Li et al. JThoracOncol 2021、cell-free DNA detection は Leighl et al. ClinCancerRes 2019 が解析。

4th-gen RET-TKI (G810 cover) : TPX-0046 (ROS1 共開発系の Repotrectinib 系列)、BOS172738、LOXO-260 が clinical evaluation 中 (Summary corpus 未収)。Selective RET inhibitor が osimertinib + RET-TKI 併用や次世代 TKI として広がる可能性を示唆。

メカニズム

RET (REarranged during Transfection) proto-oncogene は GDNF family ligands (GDNF / NRTN / ARTN / PSPN) と co-receptor GFRα1-4 を介して活性化される single-pass transmembrane RTK。生理的には enteric neurons / kidney development / spermatogenesis に必須。Fusion 形成では partner (KIF5B が最頻 / CCDC6 / NCOA4 / TRIM33 / GOPC 等) の coiled-coil / dimerization ドメインが N 末端に付加され、ligand 非依存の二量体化と恒常 kinase 活性化を惹起する。下流は RAS-RAF-MEK-ERK / PI3K-AKT-mTOR / JAK-STAT3 / PLCγ を併走的に駆動。MTC で hotspot な germline / somatic point mutation (M918T 高悪性、V804M / C634R 等) は ligand-independent activation を別経路で達成。

Selective RET-TKI の構造的優位 (Plenker et al. SciTranslMed 2017, Subbiah et al. CancerDiscov 2018) :

• ATP-binding pocket に対する selective high-affinity binding (picomolar Kd)
• VEGFR2 / KDR / SRC family を含む multi-kinase off-target を minimize → 高血圧・甲状腺機能低下症・hand-foot syndrome を顕著に低減
• 高 BBB 透過性 → intracranial ORR 82–91%、LIBRETTO-431 CNS PFS HR 0.28
• Gatekeeper V804M を立体的に回避する scaffold (multi-kinase TKI の主要弱点を克服)

Resistance スペクトル:

• Solvent-front G810R/S/C: 両 selective RET-TKI で cross-resistance major、4th-gen 開発の主要 target
• Gatekeeper V804M/L: multi-kinase TKI (vandetanib, cabozantinib) で acquired、selective TKI で克服
• Activation loop: vandetanib 耐性 case の Nakaoku NatCommun 2018
• Bypass: MET amplification、KRAS / BRAF 二次活性化、EGFR upregulation、HER2 upregulation

Variant-specific 効果: KIF5B-RET (intracellular に膜結合せず cytoplasmic / mitochondrial) vs CCDC6-RET (cytoplasmic) vs NCOA4-RET の breakpoint differences が response にどの程度影響するかは Li et al. JThoracOncol 2021 が問題提起、large prospective cohort 必要。

臨床位置づけ

1L 進行・再発 RET fusion+ NSCLC: Selpercatinib 160 mg BID が global standard (LIBRETTO-431 で chemo+pembro に PFS HR 0.46 / CNS HR 0.28 で勝利)。Pralsetinib 400 mg QD は ARROW phase II で同等の活性 (TKI-naive ORR 70% 程度) を示し代替選択肢。両 TKI は CNS active、QTc prolongation・hypertension・transaminitis・hypothyroidism のモニタリングが共通課題。Pneumonitis (特に pralsetinib) は本邦 cohort で頻度高め。

2L 以降 / TKI 耐性後: G810 耐性なら 4th-gen RET-TKI (治験)、bypass mechanism なら相応の標的薬 (MET amp に MET-TKI、KRAS-G12C なら sotorasib / adagrasib) 併用、もしくは platinum + pemetrexed ± bevacizumab に switch。Crossover 後の selpercatinib は LIBRETTO-431 control 群で実装され有効性を確認。

EGFR-TKI 耐性 bypass としての RET fusion: 1L Osimertinib 耐性で acquired RET fusion が 約5–10% に出現 (Piotrowska et al. CancerDiscov 2018)。Osimertinib + selpercatinib / pralsetinib 併用が case-based に有効、ORCHARD / SAVANNAH 等の biomarker-driven trial で前向き検証中。Real-world detection rate は Kropf-Sanchen et al. ClinLungCancer 2026 が定量。

MTC (甲状腺髄様癌) : Hadoux et al. NEnglJMed 2023 LIBRETTO-531 で selpercatinib が cabozantinib / vandetanib より明らかに優位 (PFS / ORR / 安全性すべて)、advanced RET-mutant MTC の 1L 標準。

Diagnostic: NGS (DNA + RNA、特に RNA-seq で fusion sensitivity 向上) が gold standard。FISH は KIF5B-RET 以外の partner の感度が低い。Tissue 不足例では plasma cfDNA NGS (Leighl et al. ClinCancerRes 2019) が補完。LCNEC や thymic cancer での actionable RET 検出例は Heijboer et al. JCOPrecisOncol 2025 が報告。

Open Questions

• G810 solvent-front 耐性 → 4th-gen RET-TKI: TPX-0046 / BOS172738 / LOXO-260 等の臨床開発と sequence design
• Adjuvant RET-TKI: stage IB–IIIA 完全切除後 RET fusion+ NSCLC での selpercatinib (ALINA / ADAURA echo trial design、LIBRETTO-432 など)
• CNS-only progression での continuation strategy: BBB 透過性 selective TKI 継続 + 局所治療か switch か
• RET driver overlap and bypass: MET co-alteration / acquired KRAS / 二次 EGFR upregulation の対処、dual-target combination
• EGFR + RET dual blockade: post-Osi acquired RET fusion での Osi + Selpercatinib の前向き検証 (ORCHARD / SAVANNAH)
• Variant-specific therapy: KIF5B-RET vs CCDC6-RET vs NCOA4-RET 等 fusion partner-specific signaling と TKI sensitivity の差別化
• Pediatric RET-driven cancer: infantile myofibromatosis / RET-driven rare cancers での selpercatinib 役割

重要論文 Top 10

1. ★★★★★ Drilon et al. NEnglJMed 2020 — LIBRETTO-001 Selpercatinib pivotal (TKI-naive ORR 85%, intracranial ORR 91%)
2. ★★★★★ Zhou et al. NEnglJMed 2023 — LIBRETTO-431 — chemo+pembro を PFS HR 0.46 で破る
3. ★★★★★ Subbiah et al. CancerDiscov 2018 — BLU-667/pralsetinib の selective RET drugging を確立
4. ★★★★ Kohno et al. NatMed 2012 — KIF5B-RET 同定で driver landscape 拡張
5. ★★★★ Piotrowska et al. CancerDiscov 2018 — EGFR-TKI 耐性 acquired RET fusion + dual TKI 概念実証

関連エンティティ

• 薬剤クラス: RET-inhibitor (Selpercatinib / Pralsetinib)
• 関連遺伝子: KRAS (耐性 bypass), MET
• 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 151 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Immunotherapy

• Elahi et al. NatRevImmunol 2026 — Immune regulation by erythroid cells how erythroid progenitor cells and mature red blood cells shape immunity

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

Basic-Neutrophil and myeloid cell

• Shi et al. CancerCell 2026 — Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia
• Fu et al. CancerImmunolRes 2023 — Syntaphilin regulates neutrophil migration in cancer

Basic-Oncogene and genetics

• Bandlamudi et al. CancerCell 2026 — Cancer type-specific variation in patterns of driver alterations across 50,000 tumors
• Johnson et al. CancerDiscov 2022 — Classification of KRAS-activating mutations and the implications for therapeutic intervention
• Myer et al. CancerDiscov 2022 — The genomics of colorectal cancer in populations with African and European ancestry
• Scaparone et al. CancerDiscov 2026 — EML4-ALK mediates resistance to KRAS G12C inhibition and induces an
• Wu et al. SignalTransductTargetTher 2022 — Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung

Basic-Others

• Osarogiagbon et al. AmSocClinOncolEducBook 2026 — Optimal use of targeted therapy and immunotherapy in early-stage, resectable non-small cell lung cancer
• Richter et al. CancerCell 2026 — A closed tumor-immune-brain circuit in cancer cachexia
• Zhang et al. CancerCell 2026 — Cancer cachexia a tumor-driven disorder of whole-body homeostasis
• Hadoux et al. NEnglJMed 2023 — Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer

Clinical-Epidemiology

• Fick et al. JThoracCardiovascSurg 2025 — Late recurrence of completely resected stage I to IIIA lung adenocarcinoma

Clinical-NEC

• Heijboer et al. JCOPrecisOncol 2025 — Actionable genomic alterations in large cell neuroendocrine carcinoma A european case series of patients treated with a
• Nicholson et al. JThoracOncol 2022 — The 2021 WHO classification of lung tumors impact of advances since 2015

Clinical-NSCLC-ALK

• Tanimoto et al. ClinCancerRes 2021 — Proteasome inhibition overcomes ALK-TKI resistance in ALK-RearrangedTP53-mutant NSCLC via noxa expression

Clinical-NSCLC-Driver negative

• Li et al. FrontImmunol 2026 — The application and challenges of immune checkpoint inhibitors in lung cancer therapy

Clinical-NSCLC-Driver-Other

• Park et al. CancerRes 2024 — Proteogenomic characterization reveals estrogen signaling as a target for never-smoker lung adenocarcinoma patients
• Kropf-Sanchen et al. ClinLungCancer 2026 — A retrospective, multicenter analysis within the national network genomic medicine lung cancer in germany to detect RET
• Zhou et al. NEnglJMed 2023 — First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC
• Wu et al. NEnglJMed 2026 — Selpercatinib in early-stage RET fusion-positive non-small-cell lung cancer

Clinical-NSCLC-EGFR

• Piotrowska et al. CancerDiscov 2026 — ELIOS A multicenter, molecular profiling study of patients with EGFR-mutant advanced non-small cell lung cancer treated
• Choudhury et al. ClinCancerRes 2021 — Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon
• Kim et al. FrontOncol 2026 — Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC
• Nogami et al. JThoracOncol 2022 — IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups
• Zhao et al. NatRevClinOncol 2026 — Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC-mechanisms and evolving treatment approaches

Clinical-NSCLC-ROS1

• Lin et al. ClinCancerRes 2021 — Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion-positive lung cancer

Clinical-Others

• Liu et al. NatRevMolCellBiol 2026 — Regulation and function of specialized membrane protrusions in intercellular communication