Trophoblast cell surface antigen 2, or TROP2, is a protein that is a type I transmembrane glycoprotein. It resides on the cell surface and acts as a signal transducer. Its presence on numerous solid tumors, often at significantly elevated levels, establishes it as a highly promising target for cancer therapies. Targeting TROP2 allows for the sophisticated delivery of anti-cancer agents directly to malignant cells, differentiating this strategy from older, more broadly toxic treatments. The development of TROP2-directed therapies has already transformed treatment options for several difficult-to-treat cancers.
Understanding the TROP2 Protein
TROP2 is encoded by the TACSTD2 gene and is naturally found in the human body, primarily on the surface of epithelial cells. In healthy tissues, TROP2 expression is generally low and plays a regulated role in essential biological processes. The protein’s normal function involves cell-to-cell adhesion, cell signaling, and regulating cell growth and proliferation. It is particularly important during embryonic development, where it contributes to placental tissue formation and stem cell self-renewal and regeneration. TROP2’s structure includes a short intracellular tail that acts as an intracellular calcium signal transducer, relaying messages that influence cellular behavior. This mechanism is often usurped by cancer cells when the protein is overexpressed.
How TROP2 Drives Cancer Growth
TROP2 becomes dramatically overexpressed on the surface of malignant tumors across a wide variety of solid cancers. This increase is not due to a structural gene mutation but rather a deregulation of its transcriptional control, which provides the cancer cell with a significant growth and survival advantage. TROP2 signaling activates pro-oncogenic pathways, such as the MAPK/ERK cascade, accelerating the cell cycle and promoting uncontrolled cell division. This signaling also helps cancer cells evade programmed cell death, or apoptosis. TROP2 is also implicated in metastasis by modulating cell adhesion to the extracellular matrix, promoting the migration and invasion of cancer cells and leading to a more aggressive disease course.
TROP2 as a Therapeutic Target
The high expression of TROP2 on cancer cells and its low expression on most normal tissues makes it an attractive molecular target for specialized therapies. The most advanced approach to exploit this difference is through the use of Antibody-Drug Conjugates (ADCs). An ADC is a three-part construct consisting of a monoclonal antibody, a potent chemotherapy payload, and a chemical linker connecting the two. The antibody component acts as a highly specific homing device, designed to recognize and bind only to the TROP2 protein on the cancer cell surface. Once bound, the ADC complex is internalized by the cancer cell through receptor-mediated endocytosis, where the chemical linker is broken down, typically in the acidic environment of the lysosome, releasing the toxic chemotherapy payload.
Sacituzumab govitecan (Trodelvy) is a prime example of a TROP2-targeting ADC, which uses SN-38, an active metabolite of a topoisomerase I inhibitor, as its payload. This localized delivery mechanism ensures that a high concentration of the chemotherapy is delivered directly to the tumor cells, where SN-38 induces DNA damage and subsequent cell death. This targeted approach minimizes the systemic exposure of the chemotherapy agent to healthy tissues, reducing the severe side effects often associated with traditional chemotherapy. An additional benefit is the “bystander effect,” where the released payload diffuses out of the targeted cell to kill adjacent tumor cells that may have low or no TROP2 expression, enhancing anti-tumor activity.
Clinical Testing and Relevant Cancers
Determining the TROP2 status of a patient’s tumor is a practical step in clinical oncology to guide treatment decisions. TROP2 expression is typically measured using immunohistochemistry (IHC), a laboratory technique performed on a biopsy sample that uses antibodies to visually detect the protein on the cell surface. TROP2-targeted ADCs have shown efficacy even in tumors with lower expression levels. TROP2 overexpression is observed across a broad spectrum of epithelial malignancies. It has significant clinical relevance in metastatic Triple-Negative Breast Cancer (TNBC), an aggressive subtype often lacking other targeted treatment options, and is also highly expressed in hormone receptor-positive/HER2-negative breast cancer and metastatic urothelial (bladder) cancer.
TROP2 is a focus of research and treatment in:
- Non-small cell lung cancer (NSCLC)
- Ovarian cancer
- Cervical cancer
- Some gastrointestinal cancers
In many of these cancers, TROP2 overexpression is associated with poor prognostic indicators, including increased disease aggressiveness and a higher risk of recurrence. The identification of TROP2 as a biomarker provides a standardized way to select patients who may benefit from this targeted therapy.