AKT1

AKT1 (RAC-alpha serine/threonine-protein kinase)

一行要約

AKT1 は PI3K-AKT-mTOR pathway の central serine/threonine kinase で、PI3K → PIP3 → PDK1/mTORC2 phosphorylation により活性化、下流で mTORC1 / FOXO / GSK3β / BAD / MDM2 等を制御し細胞増殖・生存・代謝を統合する。Lung cancer では稀ながら AKT1 E17K hotspot mutation が NSCLC の一部、また AKT pathway 上流 (PIK3CA, PTEN loss, RTK over-activation) の二次的活性化が IO 抵抗性 / TKI 耐性に寄与。AKT 直接阻害薬 (capivasertib) が乳癌で承認、肺癌 KEAP1/STK11 co-mutation 群での AKT 経路標的化研究進行中。

主要エビデンス

• AKT1 E17K hotspot: PH ドメイン変異で constitutive plasma membrane 局在 → 持続活性化、肺・乳・大腸癌で 1-3% 検出、basket trial 対象
• PI3K-AKT-mTOR axis 過剰活性化: NSCLC で PIK3CA mutation (2-10%) / PTEN loss / RTK 増幅と organotropic 耐性に関連
• Capivasertib + fulvestrant (CAPItello-291): HR+ breast cancer で承認、PIK3CA/AKT1/PTEN 変異 cohort で benefit
• EGFR-TKI 耐性: Osimertinib resistance で AKT pathway re-activation の bypass route
• IO 抵抗性: PI3K-AKT-mTOR 過剰活性化が tumor cell autonomous + Treg expansion を介して IO 応答低下に寄与

メカニズム

PI3K (class I) → PIP2 → PIP3 → AKT PH domain で plasma membrane recruitment → PDK1 (Thr308) + mTORC2 (Ser473) phosphorylation で full activation。Active AKT は (1) mTORC1 → S6K / 4E-BP1 経由で蛋白合成、(2) FOXO transcription factor 抑制、(3) GSK3β 阻害で β-catenin / cyclin D1 安定化、(4) BAD / Bcl-xL で apoptosis 抑制、(5) MDM2 → p53 degradation、(6) HK2 / GLUT1 で glycolysis 亢進を駆動。AKT2 / AKT3 は組織発現分布が異なり機能 redundancy あり。

臨床位置づけ

NSCLC 単独 driver としては rare (E17K 1-3%) だが、KEAP1/STK11 co-mutation 群や TKI / IO 耐性での bypass pathway として頻出。Capivasertib / ipatasertib 等 AKT inhibitor は乳癌で先行承認、NSCLC では combination 戦略が中心 (with EGFR-TKI / IO)。Mendelian randomization で IL-6 / inflammatory pathway との upstream relationship も研究対象。

Open Questions

• AKT inhibitor の NSCLC 適応: KEAP1/STK11 co-mutation 群での効果検証
• EGFR-TKI 耐性での AKT 再活性化 に対する combination 戦略
• IO + AKT 阻害: tumor cell + Treg + MDSC 多経路抑制の dose-finding
• AKT1 vs AKT2 vs AKT3 isoform-selective inhibitor の臨床価値

関連エンティティ

• 関連経路: PI3K-AKT-mTOR-pathway / MAPK-RAS-ERK-pathway / p53-pathway / Apoptosis-pathway
• 関連遺伝子: PIK3CA / PTEN / KEAP1 / STK11 / MDM2 / TP53 / EGFR
• 関連薬剤: PI3K-AKT-mTOR-inhibitor / EGFR-TKI / Osimertinib
• 関連概念: KRAS-co-mutation-landscape / IO-acquired-resistance / EGFR-T790M-resistance / Metabolic-reprogramming

関連論文

直近 30 件のみ表示中 (関連 415 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Extracellular vesicles

• Xue et al. CancerCellInt 2026 — Tissue-derived extracellular vesicles comparing ts-EVs and te-EVs in extraction, characteristics and research trends
• Li et al. JExtracellVesicles 2026 — Exosomal oleic acid promotes lymphangiogenesis and nodal metastasis in cervical cancer via the AKTmTOR pathway
• Du et al. JNanobiotechnology 2026 — Plant-derived nanovesicles the intelligent nanoplatforms for therapeutics and drug delivery

Basic-Immunotherapy

• Mao et al. FrontImmunol 2026 — MicroRNA-targeted reprogramming of CD8+ T cells against cancer
• Gupta et al. NatBiotechnol 2026 — Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models

Basic-Neutrophil and myeloid cell

• He et al. ChinMed 2026 — Shuangshen granules enhance anti-PD1 therapy effectiveness in lung adenocarcinoma by modulating myeloid-derived
• Nemilostiva et al. ClinTranslOncol 2026 — CAR-engineered neutrophils derived from induced pluripotent stem cells a new frontier in cellular immunotherapy
• Wu et al. FrontImmunol 2026 — Tumor-associated neutrophils in pancreatic ductal adenocarcinoma mechanisms and therapeutic targeting

Basic-Oncogene and genetics

• Liao et al. CancerCell 2026 — Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell
• Gu et al. CancerRes 2026 — EGFR N-glycosylation catalyzed by NDST2 promotes lenvatinib resistance in hepatocellular carcinoma
• Wong et al. Cell 2026 — A recipe for chaos extrachromosomal DNA and the hallmarks of cancer

Basic-Others

• Xu et al. CancerCell 2026 — Received 24 february 2026
• Zhang et al. CancerCell 2026 — Cancer cachexia a tumor-driven disorder of whole-body homeostasis
• Marinello et al. CancerDiscov 2026 — Approaches in non-small cell lung cancer 2
• Zhu et al. CancerMed 2026 — Harnessing gut microbiota to enhance immunotherapy in NSCLC from mechanisms to translational applications
• Clarke et al. CancerRes 2026 — Virtual tumors enable prediction of personalized therapeutic combinations for non-small cell lung cancer
• Chen et al. JImmunotherCancer 2026 — Targeting CD74 may mitigate immune-escape features and enhance BCMA CAR-T activity in preclinical models of

Basic-Tumor microenvironment

• Mahadevan et al. CancerCell 2026 — Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders
• Nigri et al. CancerDiscov 2026 — Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression

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

• 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
• He et al. JNatlCancerCent 2026 — Study of the blood-brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain

Clinical-NSCLC-EGFR

• Zhao et al. CancerTreatRev 2026 — Perioperative strategies for resectable EGFR-mutant NSCLC evidence hierarchy and clinical decision-making
• Niu et al. FrontImmunol 2026 — Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following

Clinical-NSCLC-HER2

• Tillman et al. CancerCell 2026 — Reimagining HER2 therapy bridging oncogene addiction and immune modulation

Clinical-NSCLC-ROS1

• Itchins et al. LungCancer 2026 — Real-world treatment sequencing and survival in ROS1-rearranged NSCLC across evolving treatment eras findings from the

Clinical-Novel modalities

• Li et al. MolCancer 2026 — Antibody-drug conjugates in breast cancer from mechanism to revolutionizing clinical practice

Clinical-Others

• Fan et al. LancetOncol 2026 — Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases

Clinical-SCLC

• Zhang et al. FrontImmunol 2026 — First-line serplulimab plus chemotherapy versus chemotherapy alone in small-cell lung cancer patients with brain