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 P...

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Published in:Nature communications Vol. 16; no. 1; pp. 1871 - 19
Main Authors: Yang, Xue, Ma, Xiuquan, Zhao, Tianyue, Croucher, David R., Nguyen, Elizabeth V., Clark, Kimberley C., Hu, Changyuan, Latham, Sharissa L., Bayly-Jones, Charles, Nguyen, Bao V., Budnar, Srikanth, Shin, Sung-Young, Nguyen, Lan K., Cotton, Thomas R., Chüeh, Anderly C., Lim Kam Sian, Terry C. C., Stratton, Margaret M., Ellisdon, Andrew M., Daly, Roger J.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22.02.2025
Nature Publishing Group
Nature Portfolio
Subjects:
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59/5
631/45/275
631/67/1347
631/67/395
631/80/86
82/58
82/80
96
96/1
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Ablation
Animals
Breast cancer
Ca2+/calmodulin-dependent protein kinase
Calcium
Calcium ions
Calcium Signaling
Calcium signalling
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Calmodulin
Catalytic activity
Cell activation
Cell Line, Tumor
Cell Movement - drug effects
Female
Humanities and Social Sciences
Humans
Kinases
Metastases
Metastasis
Mice
Mice, Nude
multidisciplinary
Phospholipase C gamma - metabolism
Phosphorylation
Prognosis
Protein Kinase Inhibitors - pharmacology
Proteins
Science
Science (multidisciplinary)
Signal Transduction
Therapeutic targets
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - metabolism
Triple Negative Breast Neoplasms - pathology
Tyrosine
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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 2+ 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 2+ and tyrosine kinase signals and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1. The PEAK family of pseudokinases is known to play oncogenic roles in poor-prognosis triple negative breast cancer (TNBC). Here this group identifies the role of calcium/calmodulin-dependent protein kinase 2 (CAMK2) in targeting downstream of PEAK1 thereby utilizing RA306 (CAMK2 inhibitor) to effectively attenuate TNBC xenograft growth and block metastasis as well.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-57046-8