The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance

Abstract

Therapy resistance continues to confound all available cancer therapies, including immune checkpoint inhibitors. The astonishing heterogeneity and plasticity of cancers limit long-term therapeutic benefit, and recent insights into the epigenetic heterogeneity of cancers have emphasized a need to address the underlying mechanisms driving cancer cell plasticity. Epithelial-to-mesenchymal transition (EMT)-related trans-differentiation 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. AXL receptor tyrosine kinase has a remarkably broad association with aggressive and therapy-resistant cancers and has emerged as a promising therapeutic target. Recent research has revealed that AXL is not a traditional oncogenic driver as first envisioned, but rather AXL is involved in regulating cancer cell plasticity related to the EMT program. This new knowledge 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 cancer cell plasticity and resistance to cytotoxic and targeted anti-cancer agents, as well as immune checkpoint inhibition. Several AXL-targeting agents are currently being explored in clinical trials dedicated to reverse the plasticity-mediated resistance mechanisms and potentiate current anti-cancer treatments. In this chapter, we aim to explore the unique roles of the AXL receptor tyrosine kinase in cancer cell plasticity and therapeutic resistance and discuss the alternative ways of targeting AXL in clinical trials. (Figure Presented)