The TROP2 protein is a significant focus in biological research due to its roles within the human body. Situated on the surface of cells, it acts as a communicator between a cell’s internal and external environments. TROP2 is recognized for its involvement in various biological processes, contributing to both normal health and disease development.
Understanding the TROP2 Protein
TROP2, also known as trophoblast cell surface antigen 2, is a type I transmembrane glycoprotein encoded by the TACSTD2 gene. It is composed of four distinct domains: a signal peptide, an extracellular domain, a single transmembrane helix, and a cytoplasmic tail. TROP2 is normally found in healthy epithelial tissues, where it contributes to their proper function.
TROP2’s physiological functions involve several cellular processes, including cell growth, proliferation, and adhesion. It also plays a part in cell migration, a process where cells move to new locations for tissue development and repair. TROP2 acts as an intracellular calcium signal transducer, influencing cell signaling pathways.
TROP2’s cytoplasmic tail contains sites that regulate cell cycle progression and motility. The protein also interacts with various ligands, including claudin-1 and claudin-7, components of tight junctions that help maintain epithelial barrier integrity.
TROP2’s Role in Disease
While TROP2 plays a part in normal cellular functions, its behavior can change significantly in disease states, particularly in cancer. TROP2 is frequently overexpressed in various malignant tumors, meaning it is present in much higher amounts on cancer cells compared to healthy cells. This overexpression has been observed in numerous cancer types, including breast, lung, ovarian, pancreatic, cervical, colorectal, gastric, and urothelial cancers.
The elevated presence of TROP2 on cancer cells contributes to several hallmarks of cancer progression. It can promote uncontrolled cell growth by activating specific signaling pathways, such as the ERK/MAPK pathway, influencing cell proliferation and survival. TROP2 also supports increased metastasis, the process by which cancer cells spread from the original tumor to other parts of the body. This occurs partly by regulating cell adhesion and migration, making it easier for cancer cells to detach and invade new tissues.
Beyond promoting growth and spread, TROP2 overexpression can also contribute to cancer cells’ resistance to conventional therapies. It has been linked to mechanisms that accelerate the cancer cell cycle and enhance cell survival, making these cells more resilient against treatments. For instance, in gastric cancer, high TROP2 expression has been noted, and targeting this protein can promote cancer cell death. Similarly, in cervical cancer, TROP2 overexpression is associated with a less favorable outcome and promotes the proliferation and invasion of cancer cells.
Targeting TROP2 for Therapies
Given its widespread overexpression in many cancers, TROP2 has emerged as a promising target for new therapies. A prominent strategy involves antibody-drug conjugates (ADCs), a sophisticated approach to targeted drug delivery.
The general concept of ADCs is to precisely deliver a highly potent cytotoxic agent directly to cancer cells while minimizing harm to healthy cells. An ADC consists of three main components: a monoclonal antibody designed to bind specifically to a target protein like TROP2 on cancer cells, a chemotherapy drug (payload), and a chemical linker that connects the antibody to the drug. Once the antibody binds to TROP2 on the cancer cell surface, the ADC is internalized into the cell. Inside the cell, the linker is cleaved, releasing the chemotherapy drug to exert its effect directly within the cancer cell.
Sacituzumab govitecan (Trodelvy) is a notable TROP2-targeting ADC with clinical success. It consists of an anti-TROP2 antibody linked to SN-38, an active metabolite of the chemotherapy drug irinotecan. This ADC is approved for treating metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive, HER2-negative breast cancer that has progressed after prior therapies. It also received accelerated approval for advanced urothelial cancer, though this approval was later withdrawn.
The design of sacituzumab govitecan, with its cleavable linker, allows SN-38 release inside tumor cells and in the surrounding tumor microenvironment. This mechanism, known as a “bystander effect,” means the released drug can affect neighboring cancer cells with lower TROP2 expression, enhancing anti-tumor activity. Other TROP2-targeting ADCs, such as datopotamab deruxtecan (Dato-DXd), are also under investigation, utilizing different payloads and linkers to refine targeted cancer treatment.