What are AXL inhibitors and how do they work?

In recent years, the field of oncology has witnessed remarkable advancements with the discovery and development of various targeted therapies. Among these, AXL inhibitors have emerged as a promising class of anticancer agents, offering new avenues for treatment in multiple types of malignancies. Understanding the function, mechanism, and applications of AXL inhibitors can provide deeper insights into their potential benefits and limitations in clinical settings.

AXL inhibitors specifically target the AXL receptor tyrosine kinase, which belongs to the TAM (TYRO3, AXL, and MERTK) family of receptors. AXL plays a multifaceted role in various cellular processes, including cell survival, proliferation, migration, and invasion. Notably, AXL is often upregulated in different cancer types and is associated with poor prognosis, increased metastatic potential, and resistance to conventional therapies such as chemotherapy, radiation, and targeted treatments.

The overexpression of AXL in cancer cells can trigger downstream signaling pathways that promote tumorigenesis and metastasis. For instance, AXL activation can lead to the phosphorylation of various substrates, initiating cascades such as the PI3K-AKT, RAS-RAF-MEK-ERK, and NF-κB pathways. These pathways collectively contribute to enhanced cell survival, proliferation, epithelial-mesenchymal transition (EMT), and immune evasion. Therefore, by inhibiting AXL activity, AXL inhibitors aim to disrupt these oncogenic signaling networks, thereby reducing tumor growth and spread.

AXL inhibitors work through different mechanisms to block AXL signaling. They can be classified into two main categories: small molecule inhibitors and monoclonal antibodies.

Small molecule inhibitors typically bind to the ATP-binding site of the AXL kinase domain, preventing its activation and subsequent signaling. Examples of these inhibitors include R428 (BGB324) and cabozantinib. On the other hand, monoclonal antibodies, such as YW327.6S2, target the extracellular domain of the AXL receptor, blocking its interaction with its ligand GAS6 (Growth Arrest-Specific 6). This prevents receptor dimerization and activation.

In addition to these primary mechanisms, some AXL inhibitors may have multitargeted effects, acting on other related kinases within the TAM family or other receptor tyrosine kinases, thereby exerting broader antitumor activities. However, the specificity of inhibition is crucial to minimize off-target effects and associated toxicities.

AXL inhibitors hold considerable promise for the treatment of various cancers. Their primary indication lies in combating malignancies that exhibit high levels of AXL expression or activity. This includes a range of solid tumors, such as non-small cell lung cancer (NSCLC), breast cancer, pancreatic cancer, ovarian cancer, and renal cell carcinoma. Moreover, AXL inhibitors are being investigated in hematological malignancies, including acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).

NSCLC, a leading cause of cancer-related mortality worldwide, often demonstrates resistance to conventional therapies like epidermal growth factor receptor (EGFR) inhibitors and immune checkpoint inhibitors. AXL inhibitors have shown potential in overcoming this resistance, either as monotherapy or in combination with other agents. Similarly, in breast cancer, particularly the triple-negative subtype, AXL inhibitors have demonstrated efficacy in preclinical and early clinical studies, offering a potential strategy to address therapeutic resistance and improve patient outcomes.

Emerging research also suggests that AXL inhibitors could play a role in modulating the immune microenvironment, potentially enhancing the efficacy of immunotherapies. By reducing immune evasion mechanisms, these inhibitors may potentiate the anti-tumor immune response, providing an additional rationale for their use in combination with immune checkpoint inhibitors.

In summary, AXL inhibitors represent a promising therapeutic strategy in oncology, with the potential to address treatment resistance and improve outcomes in a variety of cancers. Continued research and clinical trials are essential to further elucidate their efficacy, safety, and optimal use in different cancer settings. As our understanding of AXL signaling and its role in cancer progression deepens, the development and refinement of AXL inhibitors will likely play a pivotal role in the future of targeted cancer therapies.