2. Academic Validation
  3. Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer

Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer

  • Nat Commun. 2025 Feb 22;16(1):1871. doi: 10.1038/s41467-025-57046-8.
Xue Yang 1 2,  Xiuquan Ma 1 2,  Tianyue Zhao 1 2,  David R Croucher 3 4,  Elizabeth V Nguyen 1 2,  Kimberley C Clark 1 2,  Changyuan Hu 1 2,  Sharissa L Latham 3 4,  Charles Bayly-Jones 1 2,  Bao V Nguyen 5,  Srikanth Budnar 1 2,  Sung-Young Shin 1 2,  Lan K Nguyen 1 2 6,  Thomas R Cotton 1 2,  Anderly C Chüeh 1 2,  Terry C C Lim Kam Sian 1 2,  Margaret M Stratton 5,  Andrew M Ellisdon 1 2,  Roger J Daly 7 8
Affiliations

Affiliations

  • 1 Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.
  • 2 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
  • 3 Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
  • 4 St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
  • 5 Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA.
  • 6 South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
  • 7 Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia. roger.daly@monash.edu.
  • 8 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia. roger.daly@monash.edu.
PMID: 39984440 DOI: 10.1038/s41467-025-57046-8
Abstract

The PEAK family of pseudokinases, comprising PEAK1-3, play oncogenic roles in several poor prognosis human cancers, including triple negative breast Cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screen for PEAK1 effectors and identify calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promotes CAMK2 activation in TNBC cells via PLCγ1/CA2+ signalling and direct binding to CAMK2. In turn, CAMK2 phosphorylates PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurpose RA306, a second generation CAMK2 inhibitor. RA306 inhibits PEAK1-enhanced migration and invasion of TNBC cells in vitro and significantly attenuates TNBC xenograft growth and metastasis in a manner mirrored by PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus that integrates CA2+ and tyrosine kinase signals and identify CAMK2 as a therapeutically 'actionable' target downstream of PEAK1.

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