PAK1

Overview

PAK1 (P21-Activated Kinase 1) is a serine/threonine kinase downstream of Rac1 and Cdc42 small GTPases, promoting cytoskeletal reorganization, cell migration, and survival. In breast cancer, PAK1 is located in the 11q13/14 amplicon that characterizes the IntClust 2 high-risk subtype, where it is co-amplified with CCND1, EMSY, and RSF1.

Alterations observed in the corpus

  • PAK1 (11q14.1) is amplified as part of the 11q13/14 cis-acting cassette in IntClust 2 of the METABRIC breast cancer cohort (~2,000 tumors); co-amplified with CCND1, EMSY, and RSF1 in ER-positive, high-risk tumors PMID:22522925
  • Identified as a downstream effector of RAC1 P29S and a potential therapeutic target in melanoma (147-tumor Yale WES cohort) PMID:22842228
  • Recurrently amplified at 11q13 in esophageal adenocarcinoma (EAC) as a downstream effector of the RAC1 signaling axis (upstream regulators ELMO1, DOCK2, TRIO, TIAM1, VAV2, ECT2 are recurrently mutated) PMID:23525077
  • Co-amplification with CCND1 at 11q13–14 defines the IntClust2 breast cancer subtype (METABRIC 2,433 primary tumors); this early clonal event is associated with paradoxically low MATH heterogeneity score and resistance to neo-adjuvant cytotoxic chemotherapy. PMID:27161491
  • Focal copy gains in 5/34 ALM patients (15%); validated by qPCR in 4/5; all in BRAF/NRAS wild-type tumors (1 NF1-subtype, 4 triple-wild-type); proposed as alternate MAPK-pathway dysregulation route in acral melanoma PMID:28373299

Cancer types (linked)

  • BRCA (Breast cancer): Amplification in IntClust 2 (11q13/14-amplified ER-positive); IntClust 2 carries hazard ratio 3.62 (95% CI 1.91-6.88) in discovery cohort PMID:22522925

Co-occurrence and mutual exclusivity

  • Co-amplified with CCND1, EMSY, and RSF1 at 11q13/14 in IntClust 2 ER-positive breast cancer PMID:22522925

Therapeutic relevance

  • PAK1 kinase activity has been proposed as a therapeutic target in breast cancer; its co-amplification in the high-risk IntClust 2 subtype supports interest in PAK inhibitors, though no clinical data are in the corpus.

Open questions

  • The relative contributions of PAK1 versus CCND1, EMSY, and RSF1 within the 11q13/14 amplicon to IntClust 2 tumor behavior are not resolved PMID:22522925.

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:22842228

This page was processed by crosslinker on 2026-05-09. - PMID:23525077

This page was processed by crosslinker on 2026-05-09. - PMID:27161491

This page was processed by wiki-cli on 2026-05-14. - PMID:28373299

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