Hippo-YAP-drug-resistance-pathway

Hippo-YAP 薬剤耐性経路 (YAP-Mediated Bypass Resistance)

一行要約

YAP1/TAZ の核内活性化が EGFR-TKI、ALK-TKI、KRAS-G12C 阻害剤等の分子標的治療に対する recurrent な bypass resistance mechanism として機能し、AXL upregulation・EMT 誘導・lineage plasticity を通じて drug-tolerant persister から耐性クローンの出現を促進する経路である。

主要コンポーネントと制御構造

Hippo 経路からの YAP/TAZ 制御

Hippo-YAP-pathway の core cascade (MST1/2 → LATS1/2 → YAP1/TAZ phosphorylation → cytoplasmic retention/degradation) が正常状態で YAP/TAZ 活性を抑制する。薬剤耐性の文脈では、以下の機序により YAP/TAZ が constitutive に nuclear active となる:

• LATS1/2 不活化: Epigenetic silencing (promoter methylation)、protein degradation (NEDD4 等の E3 ligase)
• Upstream signal rewiring: 分子標的薬による driver pathway 阻害 → 代償的 Rho GTPase / integrin / mechanical signaling の活性化 → F-actin → LATS 不活化 → YAP nuclear entry
• PI3K/AKT cross-activation: PI3K-AKT-mTOR-pathway → MST1/2 inactivation → LATS bypass

YAP-TEAD 転写プログラム

Nuclear YAP1/TAZ が TEAD1-4 と complex を形成して activateする耐性関連遺伝子群:

• AXL (receptor tyrosine kinase) : YAP-TEAD の直接標的遺伝子。AXL upregulation は multiple TKI resistance の convergent mediator。AXL → GAS6 ligand → PI3K/AKT + MAPK pathway reactivation
• CTGF (CCN2)、CYR61 (CCN1) : YAP-TEAD の canonical target。ECM remodeling、survival signaling
• BIRC5 (Survivin) : Anti-apoptotic。Drug-induced apoptosis からの protection
• EMT transcription factors: SLUG (SNAI2)、ZEB1 → mesenchymal transition → drug tolerance
• Immune evasion genes: PD-L1 (一部報告)、complement regulators

AXL-YAP positive feedback

AXL 活性化 → 下流 signaling → YAP nuclear activity 促進 → AXL 転写 upregulation という positive feedback loop が形成され、耐性状態を安定化する。AXL は Gas6 (vitamin K-dependent protein) をリガンドとし、TAM receptor family (Tyro3、AXL、MerTK) に属する。

がんにおける異常と意義

EGFR-TKI 耐性における YAP

Osimertinib (第三世代 EGFR-TKI) 耐性の 約15-20% で YAP activation が検出される:

• Drug-tolerant persister (DTP) state: Osimertinib 初期治療で bulk tumor が縮小する中、少数の Drug-tolerant-persister 細胞が生存。DTP は YAP 依存的な transcriptional rewiring により quiescent だが viable な state を維持
• EMT-associated resistance: YAP → AXL → EMT program → vimentin+/E-cadherin- phenotype。Mesenchymal state の腫瘍細胞は EGFR-TKI sensitivity が低下
• Lineage plasticity: YAP は NKX2-1/TTF-1 低下と連動して lineage plasticity を促進し、adenocarcinoma → squamous / SCLC transformation の permissive context を形成

ALK-TKI 耐性における YAP

ALK-TKI (Lorlatinib 含む) 耐性でも YAP activation が報告されている:

• ALK signaling 阻害 → compensatory YAP activation → bypass resistance
• YAP-dependent AXL upregulation が recurrent theme

KRAS-G12C 阻害剤耐性における YAP

KRAS-G12C-inhibitor (sotorasib、adagrasib) 耐性の重要なメカニズムの一つ:

• KRAS-G12C inhibition → MAPK pathway suppression → adaptive YAP activation
• YAP-TEAD → parallel survival signaling → KRAS pathway independence の獲得
• KRAS-G12C inhibitor + YAP-TEAD inhibitor combination の preclinical synergy

Drug-Tolerant Persister (DTP) と YAP

DTP state は完全な耐性 (genetic resistance mutation) の前段階として、non-genetic な epigenetic/transcriptional rewiring で生存する transient state:

• YAP nuclear activity が DTP の survival program の central node
• DTP は Oxidative-phosphorylation-pathway (OXPHOS 依存性の代謝切り替え) を示すことがあり、YAP が mitochondrial metabolism gene をも制御する報告あり
• DTP state からの awakening と genetic resistance mutation の acquisition が耐性進展の two-step model

Mechanotransduction と TME

CAF (cancer-associated fibroblast) による matrix stiffening → integrin → Rho → F-actin → YAP activation。TME の physical property が腫瘍細胞の YAP 活性と薬剤耐性を extrinsic に制御する。

治療標的化

YAP-TEAD 阻害剤

Hippo-Merlin-NF2-pathway で記載の YAP-TEAD PPI 阻害剤 (TEAD palmitoylation pocket inhibitor: IK-930、VT3989 等) が TKI resistance の context でも治療標的として期待される。

AXL 阻害

• Bemcentinib (BGB324) : Selective AXL inhibitor。NSCLC Phase II (osimertinib 併用 or IO 併用)
• Cabozantinib: AXL を含む multi-kinase inhibitor。AXL-MET-VEGFR2 の同時阻害
• AXL-ADC: AXL 標的 ADC が preclinical で探索中

Combination 戦略

• EGFR-TKI + YAP-TEAD inhibitor: Osimertinib + TEAD inhibitor の preclinical synergy
• KRAS-G12C inhibitor + TEAD inhibitor: Adaptive YAP activation の preemptive blockade
• TKI + AXL inhibitor: AXL-mediated bypass の遮断
• TKI + SHP2 inhibitor: SHP2-inhibitor は MAPK pathway feedback relief を遮断し、YAP activation を間接的に抑制する可能性

DTP 標的化

DTP state の eradication strategy として:

• 代謝脆弱性 (OXPHOS 依存性) の標的化
• Epigenetic therapy (chromatin remodeling を介した DTP state の destabilization)
• Upfront combination (耐性出現前の preemptive dual pathway inhibition)

Open Questions

• YAP-TEAD 阻害剤の TKI resistance setting での臨床的有効性
• DTP → genetic resistance の transition における YAP の exact role (permissive vs instructive)
• AXL 阻害の optimal timing (upfront vs resistance 出現後)
• YAP activation の reliable clinical biomarker (IHC nuclear YAP vs gene signature)
• Lineage plasticity (adeno → SCC/SCLC transformation) における YAP の必要十分性

関連エンティティ・概念

• 遺伝子: AXL、EGFR、ALK、KRAS、MET、NF1、RB1、NKX2-1
• 経路: Hippo-YAP-pathway、Hippo-Merlin-NF2-pathway、EGFR-signaling-pathway、ALK-ROS1-signaling-pathway、RAS-GTPase-cycle-pathway、PI3K-AKT-mTOR-pathway、MAPK-RAS-ERK-pathway、Oxidative-phosphorylation-pathway
• 薬剤: EGFR-TKI、Osimertinib、ALK-TKI、Lorlatinib、KRAS-G12C-inhibitor、SHP2-inhibitor、MET-TKI
• 細胞: Drug-tolerant-persister、CAF、Cancer-stem-cell
• 方法: scRNA-seq、Spatial-transcriptomics、CRISPR-screen

関連論文

直近 30 件のみ表示中 (関連 129 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-Extracellular vesicles

• Cai et al. MolCancer 2026 — Extracellular vesicles in solid tumors from tumor ecology to engineered therapeutics
• Goh et al. NatCommun 2026 — Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles

Basic-Immunotherapy

• Marine et al. Cell 2026 — Mapping intratumor heterogeneity across layers for advancing immunotherapy
• Wang et al. Cell 2026 — CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response

Basic-Neutrophil and myeloid cell

• Lin et al. CancerDiscov 2026 — Arachidonic acid metabolism in PMN-MDSCs suppresses antitumor capacity of T cells in KRAS-mutant cholangiocarcinoma
• Lin et al. JImmunotherCancer 2026 — Integrin CD11bCD18 reprograms macrophage polarization by suppressing ERKSTAT3 signaling to enhance antitumor immunity

Basic-Oncogene and genetics

• Maurais et al. Cell 2026 — Genome instability triggers intercellular DNA transfer between human cells
• Yap et al. Cell 2026 — Targeting genomic instability in cancer
• Chan et al. Nature 2026 — Critical role for a high-plasticity cell state in lung cancer
• Franca et al. Nature 2026 — A mechanism for adaptive genome regulation in cancer

Basic-Others

• Winslow et al. CancerDiscov 2026 — A roadmap to transform lung cancer outcomes priorities in biology, therapeutic innovation, early detection, prevention
• Winkler et al. Cell 2026 — Cancer neuroscience the past, the present, and the road ahead
• Rochelle et al. JClinInvest 2026 — Leveraging factors that control alveolar epithelial cell fate enables large-scale expansion for lung tissue engineering
• Zhang et al. JImmunotherCancer 2026 — HDAC inhibitors reverse YAP-driven immune resistance in NSCLC mechanistic and translational evidence
• Jimenez-Castano et al. NatCancer 2026 — Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity
• Saviano et al. NatRevCancer 2026 — Claudin proteins as emerging therapeutic targets for solid tumours

Basic-Tumor microenvironment

• Liu et al. CancerCell 2026 — Molecular phenotypes and spatial archetypes A new framework for cancer-associated fibroblasts
• Nigri et al. CancerDiscov 2026 — Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression
• Reyes et al. Cell 2026 — Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition
• Garate-Soraluze et al. JImmunotherCancer 2026 — Cancer-associated fibroblast targeting therapies as a tool to enhance responses to radiotherapy and immunotherapy
• Skrupskelyte et al. Nature 2026 — Precancerous niche remodelling dictates nascent tumour persistence

Clinical-Mesothelioma

• Lopez et al. Med 2026 — Lago-Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy strategies to restore

Clinical-NSCLC-Driver-Other

• Wang et al. Cell 2026 — Farnesylation-driven KRAS phase separation promotes colon tumor growth
• Canaslan et al. CritRevOncolHematol 2026 — From G12C to pan-RAS the expanding therapeutic landscape of KRAS-mutant NSCLC
• Vitale et al. CritRevOncolHematol 2026 — Targeting KRAS G12C in non-small cell lung cancer breakthrough inhibitors and combination approaches

Clinical-Novel modalities

• Andersson-Rolf et al. NatRevMolCellBiol 2026 — New developments and applications of human organoids

Clinical-Others

• Luo et al. NatRevCancer 2026 — N6-Methyladenosine an RNA modification as a central regulator of cancer

Clinical-SCLC

• Campisi et al. CancerCell 2026 — Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer
• Guan et al. CritRevOncolHematol 2026 — Overcoming immunotherapy resistance in extensive-stage small cell lung cancer insights into mechanisms and therapeutic