Lukas Morehead

 Background Triple Negative Breast Cancer (TNBC) is a rare, aggressive form of breast cancer prone to high rates of metastasis.^{1, 2} Despite only comprising about 10-15% of breast cancer diagnoses, TNBC has disproportionate high rates of recurrence and poor prognosis.¹ Over the last few decades, therapies utilizing antibody and ligand-based targeted approaches have become prevalent areas of research in cancers that show limited response to traditional therapy. CUB Domain-Containing Protein 1 (CDCP1) is cell-surface transmembrane glycoprotein that is upregulated in breast cancer and thought to contribute to metastasis and the poor prognosis of TNBC.³ Through study of the underlying mechanism of CDCP1, we can target neoplastic cells and create new therapies that improve clinical outcomes of TNBC.

Objective In this narrative review, we define the mechanisms through which CDCP1 is implicated in the progression of TNBC and the rational design for antibody-based therapy that targets the CDCP1 axis.

Search Methods The PubMed Database was searched using keywords “CDCP1”, “TNBC”, “antibody”, “ligand”, and “ADC”.

Results CDCP1 is strongly upregulated in TNBC and implicated in survivability. 70% of TNBC cells had medium or high levels of CDCP1 expression and the hazard ratio for survivability was 2.13 in multivariate analysis when comparing high to low CDCP1 transcript count.^{3, 4} CDCP1 is a potent metabolism modulator and activates the SRC kinase axis. In mechanistic studies, it was found CDCP1 directly upregulates oxidative phosphorylation through complex 1 activity, increasing basal respiration, maximal respiration, and ATP production rates.⁵ CDCP1 also promotes fatty acid oxidation and reduces lipid-droplet abundance.^{3, 5} In a related downstream axis, CDCP1 activates SRC, RAC1, and ARHGEF7 which are required for the binding of HGF to MET receptors which promotes lamellipodia formation and propagates metastasis.⁶ Controlling metastasis is paramount as patient survival drops from 91.2% to 11.5% when comparing localized to metastasized TNBC.⁵ CDCP1 also strongly interacts with the immune system to increase immune checkpoints, decreasing tumor immune surveillance. CDCP1 binds with CD6, expressed on NK, NKT, and CD8+ T cells, to reduce perforin release and immune infiltration.⁷ In a gene co-expression study, there was a positive correlation between CDCP1 and PD-L1, B7-H3, and B7-H4, which are commonly used as markers of immune checkpoint expression. Furthermore, CDCP1 (0.763) was found to be a stronger predictor of immunotherapy response than PD-L1 (0.649), which is traditionally used.³ Interfering with the CDCP1 immune axis may be of particular importance as a 10% increase in tumor-infiltrating lymphocytes leads to a 13-15% relative risk reduction.^{1, 2} Accordingly, early studies have indicated CDCP1 may be of therapeutic value. In mice models, CDCP1 antibodies (ch10D7) conjugated to a zirconium-89 radiotracer improved tumor detection from 8.6% to 16.5%. In the same study, mice models treated with ch10D7 conjugated to an antimitotic agent (MMAE) had survivability improvements to 111 days from 50 days (control).⁴

Conclusion TNBC is a rare, deadly form of breast cancer that has limited therapeutic options. CDCP1 is being explored as a potential new target and is thought to control the progression of TNBC stemming from three mechanisms: regulating immune response, upregulating metabolism, and initiating metastasis. Early studies show efficacy in improving imaging and survivability in animal models, however further mechanistic and human trials must be conducted to explore CDCP1 antibody-based therapies.

Works Cited

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2. Derakhshan F, Reis-Filho JS. Pathogenesis of Triple-Negative Breast Cancer. Annu Rev Pathol. 2022;17:181-204. doi:10.1146/annurev-pathol-042420-093238
3. Zhao J, Mei J, Wang F, et al. Overexpression of CDCP1 is Associated with Poor Prognosis and Enhanced Immune Checkpoints Expressions in Breast Cancer. J Oncol. 2022;2022:1469354. Published 2022 Aug 31. doi:10.1155/2022/1469354
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