Targeting AXL in NSCLC

Abstract

State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL’s role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL’s role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

“…Overexpression of AXL has been correlated with disease aggressiveness in many cancers. This includes cancers of breast ( 56 – 58 ), lung ( 53 , 59 – 62 ), gastrointestinal ( 63 – 66 ), head and neck ( 67 – 69 ), hepatocellular carcinoma ( 70 – 72 ), renal cell carcinoma (RCC) ( 73 – 77 ), gynecological carcinoma ( 78 – 81 ), gliomas ( 82 ) pancreatic cancer ( 83 , 84 ), and thyroid carcinoma ( 85 ). Overexpression of AXL has also been reported in several types of sarcomas ( 86 – 89 ), in acute myeloid leukemia (AML), and other hematologic malignancies ( 52 , 90 , 91 ).…”

“…Due to the pro-tumoral, pro-metastatic, and treatment resistance roles of AXL, numerous therapeutic interventions targeting AXL have been designed and investigated. Several investigators have covered this topic well to which the readers can be referred ( 7 , 21 , 22 , 30 , 36 – 38 , 53 , 119 , 172 , 195 ).…”

The effects of epithelial–mesenchymal transitions in COPD induced by cigarette smoke: an update

“…[ 186 – 189 ]. AXL is a tyrosine kinase receptor that has been reported as an oncogene in a range of cancers, including NSCLC [ 190 ]. Cabozantinib, a tyrosine kinase inhibitor that includes AXL, has been reported to reverse EMT-associated osimertinib resistance in NSCLC [ 191 ].…”

Axl contributes to efficient migration and invasion of melanoma cells

“…Among three members, Axl is the most studied and has been shown to be elevated in many cancers including melanoma, breast, lung, ovary, pancreas, and prostate [8][9][10][11][12]. Axl can be activated when its ligand, growth arrest-specific protein (Gas6), binds on resulting in a cascade of downstream signaling pathways [13]. Gas6 consists of three major domains [14].…”