The AXL protein is a receptor tyrosine kinase (RTK) found on the surface of cells. RTKs are proteins that transmit signals from outside the cell to its interior, influencing various cellular activities. AXL’s function involves binding to specific growth factors, such as Growth Arrest-specific 6 (GAS6), triggering a cascade of events inside the cell. This signaling process influences biological processes, including cell proliferation, migration, differentiation, and survival. The presence and activity of AXL are important for maintaining normal bodily functions.
Normal Cellular Functions
AXL protein contributes to several physiological processes in healthy cells and tissues. It participates in fundamental cellular activities like cell survival and proliferation. AXL also influences cell migration, involved in wound healing and immune responses. The protein is expressed in various normal tissues, including bone marrow stroma and myeloid cells.
AXL plays a role in the immune system, particularly in regulating inflammatory responses. It helps to dampen excessive inflammation, which can protect normal cells from damage. AXL also assists in the clearance of apoptotic cells, a process called efferocytosis, where dead cells are removed by phagocytes like macrophages.
AXL’s Role in Disease Development
Dysregulation or overexpression of the AXL protein has been linked to the development and progression of various diseases. AXL’s involvement in cancer is particularly well-established, where its altered activity can promote tumor growth by increasing the proliferation and survival of cancer cells. AXL also contributes to metastasis, the spread of cancer, by influencing cell migration and invasion.
The AXL pathway plays a role in cancer cells developing resistance to chemotherapy and targeted therapies, making treatments less effective. This resistance can lead to unfavorable clinical outcomes in various cancers, including gastrointestinal cancers. AXL’s activation can stimulate survival pathways in cancer cells, helping them endure stressful conditions like drug exposure.
Beyond cancer, AXL has been implicated in other conditions. Its pathway can facilitate viral infections, such as Zika and SARS. AXL also contributes to inflammatory diseases, where its altered signaling can lead to issues such as basal cell proliferation in the lungs during inflammatory conditions.
Therapeutic Strategies Targeting AXL
Given AXL’s involvement in disease, especially cancer, researchers are exploring therapeutic strategies to modulate its activity. The goal is to inhibit AXL to overcome drug resistance and prevent cancer metastasis. Various types of AXL inhibitors are under investigation, including small molecule inhibitors and antibodies. Small molecule inhibitors aim to block AXL’s enzymatic activity inside the cell.
Antibody-based therapies target the extracellular part of the AXL receptor. These strategies aim to disrupt AXL signaling, either by directly blocking its activation or by marking AXL-expressing cells for destruction. The rationale for targeting AXL is to re-sensitize tumors to existing treatments and suppress the immune-evading mechanisms employed by cancer cells.
Challenges in AXL-targeted therapies include understanding the precise mechanisms of AXL activation in different cellular contexts and identifying the optimal combinations with other anti-cancer drugs. Despite these challenges, ongoing research and clinical trials are exploring AXL inhibitors as single agents or in combination with chemotherapy, immunotherapy, or radiotherapy. This aims to improve treatment outcomes for patients, particularly in cases of drug-resistant cancers and certain viral infections.