Ryan Pohorenec, MSc

Background: Breast cancer represented 31% of new cancer diagnoses and 15% of cancer-related deaths among women in the United States in 2023,¹ with an incidence of 99.2–133.7 per 100,000.² Triple-Negative Breast Cancer (TNBC) is a molecular subtype found in 10% of invasive breast cancers that is characterized by the absence of estrogen receptor (ER^–), human epidermal growth factor receptor 2 (HER2^–), and progesterone receptor (PR^–) on the tumor cell surface.² Absence of the HR, as a canonical chemotherapeutic target, in TNBC complicates treatment and is consistent with the 17% reduction in the 5-year survival rate relative to HR⁺/HER2^– breast cancers.² Significant efforts have been made in recent decades to develop novel TNBC therapies, which led to the emergence of new strategies.³ Despite these advances, the clinical management of metastatic TNBC (mTNBC) remains a challenge. Elucidation of the role of trophoblast cell surface antigen 2 (TROP2) in the acquisition of metastatic phenotype in various cancer types culminated in the U.S. Food and Drug Administration’s 2020 approval of Sacituzumab Goveitecan (Trodelvy^®) for refractory mTNBC, which conferred 4.3 – 6.3 month (95% CI) longer survival times relative to monotherapy in the phase III ASCENT trial.⁴

Objectives: In this review, the mechanisms of TROP2-mediated tumor metastasis are summarized to provide a rational basis for the use of anti-TROP2 IgG-SN38 as an antibody-drug conjugate (ADC) therapeutic for mTNBC.

Methods: A total of 8,703 results in the PubMed database published between 2018 and 2024 were retrieved on 13 January 2024 using the search terms “TROP2” or “TNBC”.

Results: TROP2 has been implicated in the disruption of intercellular junctions, induction of epithelial-mesenchymal transition (EMT), alteration of cytoskeletal dynamics, and activation of the JAK/STAT signaling pathway. Activation of TROP2 is initiated by phosphorylation by PKCα/δ. The interaction between TROP2 and claudin-7 is disrupted, leading to mislocalization of an important contributor to tight junctions away from the cell surface.⁵ Colocalization of galectin-3 with TROP2 at the cell surface enhances PKCα/δ activity and recruits ADAM10 and -secretase, which proteolytically cleave pTROP2. Translocation of the intracellular TROP2 fragment, β-catenin, and transcription factor 4 (TCF4) to the nucleus induces ZEB1 expression, leading to downstream inhibition of the CDH1 gene encoding the E-cadherin and destabilization of adherens junctions.^6,7 Increased adherence to the extracellular matrix (ECM) is facilitated by TROP2-induced EMT through upregulation of fibronectin.⁸ pTROP2 assembles a signaling super-complex composed of Na⁺/K⁺-ATPase, CD9, PKCα, and cofilin that results in cytoskeletal remodeling, enhancing cellular motility through the ECM.⁹ TROP2 also promotes proliferation, ECM remodeling, angiogenesis, and metabolic reprogramming through activation of the JAK/STAT signaling pathway. ¹⁰ Binding of Sacituzumab Goveitecan to TROP2 triggers intracellular internalization of the antibody-receptor complex, functionally deactivating TROP2. Release of the covalently bound topoisomerase inhibitor (SN-38) from the antibody-drug conjugate via cellular esterases leads to tumor cell death.^4,11

Conclusion: TROP2 facilitates the development of cancer hallmarks and aggressive tumor behavior, and can be therapeutically inhibited by ADCs. Given that TROP2 is upregulated in various cancer types, there is new hope for treatment of other pharmacologically challenging cancers with enhanced tumor cell specificity using this platform.

Works Cited:

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