The PEAK family of pseudokinases, comprising PEAK1-3, are oncogenic scaffolding proteins that undergo tyrosine phosphorylation and homo- and heterotypic association to assemble protein complexes with contrasting signal outputs. PEAK1 is implicated in several poor prognosis human cancers, including triple negative breast cancer (TNBC), but therapeutic targeting of this pseudokinase is challenging due to its lack of catalytic activity. To address this, we undertook a proteomics screen, identifying calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G as interactors for PEAK1-containing homo- and heterotypic complexes. PEAK1 promoted CAMK2D/G activation in TNBC cells via a novel feed-forward mechanism involving PEAK1/PLCg1/Ca2+ signalling and direct binding via a consensus CAMK2 interaction motif in the PEAK1 N-terminus. In turn, CAMK2 phosphorylated PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurposed RA306, a second generation CAMK2 inhibitor under pre-clinical development for treatment of cardiovascular disease. RA306 demonstrated on-target activity against CAMK2 in TNBC cells and inhibited PEAK1-enhanced migration and invasion in vitro. Moreover, RA306 significantly attenuated TNBC xenograft growth and blocked metastasis in a manner mirrored by CRISPR-mediated PEAK1 ablation. Overall, these studies establish PEAK1 as a fundamental cell signalling nexus, identify a novel mechanism for regulation and integration of Ca2+ signalling and identify CAMK2 as an ‘actionable’ target downstream of PEAK1.