The Role of Axl Receptor Tyrosine Kinase in Tumor Cell Plasticity and Therapy Resistance

In spite of the advances in cancer treatment over several decades, resistance to antitumor therapy continues to confound current treatment strategies. Recent insights into the epigenetic heterogeneity of cancer have emphasized a need to address the underlying mechanisms driving tumor cell plasticity. Epithelial-to-mesenchymal transition (EMT)-related transdifferentiation programs are prevalent in aggressive tumors displaying a drug-resistant, invasive, and immune-evasive phenotype. Novel therapeutically actionable targets are needed in order to disable tumor plasticity mechanisms. The Axl receptor tyrosine kinase has a remarkably broad association with aggressive and therapy-resistant cancers, and the understanding that Axl is not a traditional oncogenic driver as first envisioned, but rather involved in regulating tumor cell plasticity related to the EMT program has provided a framework to understand the role of Axl-mediated signal transduction in cancer. Accordingly, a growing number of studies have demonstrated that Axl signaling is required to maintain tumor plasticity and resistance to cytotoxic and targeted anticancer agents. Novel Axl-targeting agents are emerging, facilitating clinical translation of novel combination approaches dedicated to reverse the plasticity-mediated resistance mechanisms and potentiate current anticancer treatments. In this chapter, we describe the unique roles of the Axl receptor tyrosine kinase in tumor cell plasticity and therapeutic resistance and provide an update on Axl-targeting agents entering clinical trials.