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

Xue Yang1,2, Xiuquan Ma1,2, Tianyue Zhao1,2

  • 1Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.

Nature Communications
|February 21, 2025
PubMed

Insights

PEAK1 pseudokinases drive triple negative breast cancer (TNBC) by activating CAMK2. Inhibiting this PEAK1/CAMK2 interaction with RA306 reduces TNBC growth and metastasis, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PEAK1-3 pseudokinases are oncogenic in poor-prognosis cancers like triple-negative breast cancer (TNBC).
  • Targeting pseudokinases is difficult due to their lack of catalytic activity.
  • Identifying downstream effectors is crucial for therapeutic development.

Purpose of the Study:

  • To identify PEAK1 effectors in TNBC.
  • To elucidate the PEAK1 signaling pathway.
  • To evaluate RA306 as a therapeutic agent targeting the PEAK1/CAMK2 axis.

Main Methods:

  • Screening for PEAK1 interacting proteins.
  • Investigating calcium signaling pathways (PLCγ1/Ca2+).
  • Utilizing a second-generation CAMK2 inhibitor (RA306) in vitro and in vivo TNBC models.

Main Results:

  • CAMK2D and CAMK2G identified as PEAK1 effectors.
  • PEAK1 activates CAMK2 via PLCγ1/Ca2+ signaling and direct binding.
  • CAMK2 phosphorylates PEAK1, enhancing PEAK1/PEAK2 association and oncogenic signaling.
  • RA306 inhibits TNBC cell migration/invasion and attenuates xenograft growth/metastasis.
  • PEAK1 ablation mirrors RA306 effects.

Conclusions:

  • PEAK1 acts as a signaling nexus integrating calcium and tyrosine kinase pathways.
  • CAMK2 is a key downstream effector and a therapeutically actionable target in TNBC.
  • Pharmacologic inhibition of CAMK2 with RA306 shows therapeutic potential against TNBC.

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