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

Xue Yang, Xiuquan Ma, Tianyue Zhao, David R. Croucher, Elizabeth V. Nguyen, Kimberley C. Clark, Changyuan Hu, Sharissa L. Latham, Charles Bayly-Jones, Bao V. Nguyen, Srikanth Budnar, Sung-Young Shin, Lan K. Nguyen, Thomas R. Cotton, Anderly C. Chüeh, Terry C. C. Lim Kam Sian, Margaret M. Stratton, Andrew M. Ellisdon and Roger J. Daly ()
Additional contact information
Xue Yang: Monash Biomedicine Discovery Institute
Xiuquan Ma: Monash Biomedicine Discovery Institute
Tianyue Zhao: Monash Biomedicine Discovery Institute
David R. Croucher: Garvan Institute of Medical Research
Elizabeth V. Nguyen: Monash Biomedicine Discovery Institute
Kimberley C. Clark: Monash Biomedicine Discovery Institute
Changyuan Hu: Monash Biomedicine Discovery Institute
Sharissa L. Latham: Garvan Institute of Medical Research
Charles Bayly-Jones: Monash Biomedicine Discovery Institute
Bao V. Nguyen: University of Massachusetts
Srikanth Budnar: Monash Biomedicine Discovery Institute
Sung-Young Shin: Monash Biomedicine Discovery Institute
Lan K. Nguyen: Monash Biomedicine Discovery Institute
Thomas R. Cotton: Monash Biomedicine Discovery Institute
Anderly C. Chüeh: Monash Biomedicine Discovery Institute
Terry C. C. Lim Kam Sian: Monash Biomedicine Discovery Institute
Margaret M. Stratton: University of Massachusetts
Andrew M. Ellisdon: Monash Biomedicine Discovery Institute
Roger J. Daly: Monash Biomedicine Discovery Institute

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57046-8

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