Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer
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/Ca<sup>2+</sup> 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 Ca<sup>2+</sup> and tyrosine kinase signals and identify CAMK2 as a therapeutically 'actionable' target downstream of PEAK1.
Authors
- Srikanth Budnar (ORCID: https://orcid.org/0000-0002-8951-9081)
- Thomas R. Cotton (ORCID: https://orcid.org/0000-0001-6709-9218)
- Bao V. Nguyen (ORCID: https://orcid.org/0000-0002-4693-3098)
- Xue Yang (ORCID: https://orcid.org/0000-0002-1016-5584)
- Elizabeth V. Nguyen (ORCID: https://orcid.org/0000-0002-6495-7827)
- Terry C.C. Lim Kam Sian (ORCID: https://orcid.org/0000-0001-7038-1214)
- Andrew M. Ellisdon (ORCID: https://orcid.org/0000-0002-2248-9914)
- Anderly C. Chüeh (ORCID: https://orcid.org/0000-0003-1140-5516)
- Lan K. Nguyen (ORCID: https://orcid.org/0000-0003-4040-7705)
- Sharissa L. Latham (ORCID: https://orcid.org/0000-0003-1128-5315)
- David R. Croucher (ORCID: https://orcid.org/0000-0003-4965-8674)
- Xiuquan Ma (ORCID: https://orcid.org/0000-0001-7227-1289)
- Kimberley C. Clark (ORCID: https://orcid.org/0000-0001-6277-8297)
- Roger J. Daly (ORCID: https://orcid.org/0000-0002-5739-8027)
- Margaret M. Stratton (ORCID: https://orcid.org/0000-0003-2686-9022)
- Charles Bayly-Jones (ORCID: https://orcid.org/0000-0002-7573-7715)
- Changyuan Hu (ORCID: https://orcid.org/0000-0002-7193-1537)
- Tianyue Zhao
- Sung‐Young Shin (ORCID: https://orcid.org/0000-0002-1447-9687)
Institutions
- Garvan Institute of Medical Research (AU)
- University of Massachusetts Amherst (US)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- UNSW Sydney (AU)
- Monash Health (AU)
- St Vincent's Clinic (AU)
- Centre for Cancer Biology (AU)
- Monash University (AU)
- The University of Adelaide (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41467-025-57046-8
- Citations
- 5
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- U.S. Department of Health and Human Services
- Victorian Cancer Agency
- Marshfield Clinic Research Foundation
- National Breast Cancer Foundation
- Monash University
- Department of Health, State Government of Victoria
- National Institutes of Health
- University of Massachusetts Amherst
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council