AKT1

Overview

AKT1 is a central PI3K/AKT pathway kinase whose activating mutations (notably E17K) drive PI3K signaling and have been implicated as bypass-resistance mechanisms to targeted therapies.

Alterations observed in the corpus

  • AKT1 was altered in 2.7% (11/414) of FGFR2/3-altered urothelial carcinomas as part of the PI3K-pathway co-alteration spectrum PMID:37682528.
  • One patient acquired an activating AKT1 mutation on erdafitinib (detected in serial cfDNA, 1/27) as a putative bypass resistance mechanism PMID:37682528.
  • AKT1 point mutations exclusive to MG2 meningiomas (13%) in a 201-patient integrative molecular classification study; MG2 is the NF2-wildtype benign group enriched for TRAF7/AKT1/KLF4/SMO mutations PMID:34433969.
  • AKT1 deletions acquired at relapse in fusion-positive rhabdomyosarcoma (FP-RMS) lacking other major secondary events, identified by ctDNA liquid biopsy (n=35 tumor pairs) PMID:37730754.
  • AKT1 was not somatically mutated in 207 high-grade soft tissue sarcomas (sarc_mskcc); however, elevated phospho-AKT (Ser473/Thr308) served as a pathway readout in PIK3CA-mutant myxoid/round-cell liposarcoma (MRLS) tumors, particularly in helical-domain (E545K) mutants PMID:20601955.
  • Identified as mutated in LUAD (TSP, n=188); part of mTOR pathway altered in >30% of tumours; fell below formal significance threshold given cohort size. PMID:18948947
  • AKT1 assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • AKT1 mutation identified in ARID1A-mutant ovarian cancer functional genomics screen as a synthetic lethal vulnerability with BET bromodomain inhibition PMID:22037554
  • Somatic mutations identified in AKT1 in breast cancer WES of 100 tumors, contributing to PI3K/AKT pathway activation PMID:22722201
  • AKT1 alterations identified in breast cancer WES/WGS of 103 tumors (Broad Institute), implicating AKT pathway in breast tumorigenesis PMID:22722202
  • Mutated in breast cancer (TCGA, 510 tumors); AKT1 alterations identified as part of the PIK3CA/AKT signaling axis in luminal subtypes PMID:23000897
  • Copy number gain in OSCC; part of the PI3K/AKT mitogenic signaling pathway, altered in 63% of OSCC tumors overall in the hnsc_mdanderson_2013 cohort PMID:23619168
  • Mutation in 2% of high-grade bladder cancers; AKT1-mutant tumors predicted to be sensitive to MK-2206 AKT inhibition (vs TSC1-loss which confers resistance at S6/4EBP1 level) PMID:23897969
  • Sporadic alteration identified in a biliary tract cancer prevalence-screen panel (intrahepatic cholangiocarcinoma/gallbladder carcinoma cohort); included as a candidate driver in the extended sequencing panel PMID:24185509
  • Phosphorylated at S473 in GBC cells in response to paracrine rh-SEMA7A; PI3K inhibition by LY294002 blocked downstream p-EP300 S1834, placing AKT1 upstream of EP300 in the SEMA7A/ITGB1 signaling cascade PMID:24997986
  • Recurrent mutation in 2% of muscle-invasive urothelial carcinoma (UCB) in the PI3K/AKT pathway; co-occurring with PIK3CA and TSC1 alterations (6% each) PMID:25092538
  • PI3K/AKT pathway mutations (PTEN, AKT1/2, PAX8/PPARG) account for 4.5% (18/402) of papillary thyroid carcinomas in the TCGA PTC cohort PMID:25417114
  • Activating p.E17K mutation in metastatic castration-resistant prostate cancer (mCRPC); part of PI3K/AKT pathway alterations in 71.3% of cases PMID:26000489
  • Recurrent E17K mutation nominated as a biomarker for combination MEK + PI3K/AKT/mTOR therapy in cutaneous melanoma PMID:26091043
  • Cross-disease context: SF3B1-driven alternative splicing targets AKT1 in other cancers (e.g. breast cancer); used as comparison context in a CLL study where SF3B1-K700E activates mTORC1/MYC via NFATC1 mis-splicing rather than AKT1 PMID:26200345
  • Highest average pAKT-S473 and pAKT-T308 levels of any breast cancer subtype detected by RPPA in ILC — comparable to HER2+ and Basal-like IDC — nominating PI3K/AKT pathway inhibition as a particularly attractive therapeutic strategy for this Luminal A disease PMID:26451490
  • E17K hotspot activating mutation in 2 prostate cancer tumors; D323Y in 1 tumor (likely activating, structurally adjacent to E17K in 3D); part of ~25% PI3K/MAPK pathway actionable alterations in primary prostate cancer PMID:26544944
  • Recurrent p.E17K mutation identified in lung adenocarcinoma (NSCLC) via pan-lung WES analysis; mutually exclusive with other RTK/Ras/Raf activating events PMID:27158780
  • Mutually exclusive with PIK3CA, PIK3R1, and FOXO3 mutations in breast cancer; identified as a PI3K-pathway co-exclusion partner in 2,433-sample METABRIC cohort PMID:27161491
  • PI3K/mTOR pathway alteration observed in cisplatin-resistant germ cell tumors alongside MTOR, TSC1, TSC2 events PMID:27646943
  • AKT1 identified as a significantly mutated driver in metastatic breast cancer (mBC); also mutated in early breast cancer (eBC) — no significant enrichment in the metastatic setting PMID:28027327
  • 2 E17K mutations in LUAD patients; 1 of 2 derived 12-month clinical benefit on matched therapy (MSK-IMPACT cohort, n=860) PMID:28336552
  • Upregulated expression in Cluster 2 of cholangiocarcinoma (p < 0.05) alongside CTNNB1 and WNT5B PMID:28667006
  • PIK3CA/AKT1/AKT3/PIK3R1 predominantly carry known activating hotspot mutations in prostate cancer; one patient acquired a PIK3CA E545K hotspot ~3 years after prostatectomy, illustrating late-emergent actionable events PMID:28825054
  • Right-sided enrichment of AKT1 mutations observed in a 1,122-patient mCRC panel sequencing cohort PMID:29316426.

Cancer types (linked)

  • BLCA / UTUC — PI3K co-alteration and acquired on-treatment resistance mutation PMID:37682528.
  • MNG — AKT1 point mutations in 13% of MG2 meningiomas; potentially targetable with AKT-directed therapies PMID:34433969.
  • RMS (fusion-positive) — AKT1 deletions acquired at relapse; detected by ctDNA PMID:37730754.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Acquired AKT1 activation is a candidate bypass resistance mechanism to erdafitinib; supports rationale for AKT or PI3K-pathway combinations PMID:37682528.

Open questions

  • Whether AKT1-directed combinations can prevent or reverse erdafitinib resistance in FGFR3-altered UC is untested PMID:37682528.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:18948947

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22037554

This page was processed by crosslinker on 2026-05-14. - PMID:22722201

This page was processed by crosslinker on 2026-05-14. - PMID:22722202

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:23619168

This page was processed by crosslinker on 2026-05-14. - PMID:23897969

This page was processed by crosslinker on 2026-05-14. - PMID:24185509

This page was processed by crosslinker on 2026-05-14. - PMID:24997986

This page was processed by crosslinker on 2026-05-14. - PMID:25092538

This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26200345

This page was processed by crosslinker on 2026-05-14. - PMID:26451490

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by entity-page-writer on 2026-05-15. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:27161491

This page was processed by entity-page-writer on 2026-05-15. - PMID:27646943

This page was processed by entity-page-writer on 2026-05-15. - PMID:28027327

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15.