Targeting TUBB2B: Exploiting brain metastatic vulnerabilities in triple-negative breast cancer

Breast cancer remains a leading cause of cancer-related mortality, with brain metastasis contributing significantly to poor outcomes. Triple-negative breast cancer (TNBC) exhibits aggressive behavior, a high incidence of brain metastasis, and limited therapeutic options, underscoring the urgent need for novel strategies targeting brain metastatic vulnerabilities. We recently established an in vivo brain metastasis model using an optimized intracarotid injection method and integrated bioinformatics to identify drivers of metastatic colonization. TUBB2B, a beta-tubulin isoform involved in axon guidance during neural development, was identified as a novel TNBC gene promoting brain metastatic outgrowth (He et. al. J Exp & Clin Can Res, 2025). In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells, suggesting a feed-forward interaction that promotes brain metastatic colonization. Here, we further evaluated the therapeutic potential of targeting TUBB2B and investigated its role in mediating TNBC-stromal cell interactions in the brain niche. Methods: Patient-derived organoid (PDO) models were established to evaluate TUBB2B knockdown effects on tumor growth and survival. 3D co-culture models were employed to examine carcinoma-astrocyte/neuron gap junctions and dye transfer assays were used to assess intercellular communication. Preclinical studies were performed to test the effect of TUBB2B inhibition alone and in combination with the brain-penetrant Akt inhibitor (Akti) GDC-0068 (Ipatasertib), currently in Phase 3 trials. Results: TUBB2B knockdown significantly inhibited PDO growth in two independent models and reduced dye transfer between TNBC cells and astrocytes, suggesting impaired gap junction communication. Combining TUBB2B depletion with Akti markedly reduced TNBC cell viability compared to single-agent treatment. Ongoing studies are testing the combination effects of siTUBB2B-gold nanoparticles with Akti (GDC-0068 and Capivasertib) in preclinical animal models. Conclusions: TUBB2B plays a critical role in TNBC brain metastasis and represents a promising therapeutic target, particularly in combination with Akt pathway inhibition. These findings may inform future clinical strategies for TNBC patients with brain metastases. This work is supported by National Natural Science Foundation of China (81972781, 82273470) and City University of Hong Kong (9609316, 9680348). This abstract was proofread using AI-assisted tools.