Below is a collection of independent, peer-reviewed publications providing evidence for the role of AXL biology in driving immune suppression and tumor immune evasion as well as therapy resistance and cancer spread.
Bemcentinib restores response in STK11m NSCLC patients
Bemcentinib reverses immune suppression
Small molecule Axl inhibition targets tumor immune suppression and enhances chemotherapy in pancreatic cancer
Ludwig, K.F., et al. Cancer Res; 78(1); 246–55 (2017)
The article provides evidence that Axl is associated with poor outcomes in pancreatic cancer and uniquely links drug resistance and immune evasion. Treatment with bemcentinib blocks aggressive traits of pancreatic cancer & enhances activity of gemcitabine. Bemcentinib drives tumour cell differentiation and provokes an immune stimulatory microenvironment. Bemcentinib is also shown to reduce expression of Arginase-1 - a key player in immune-suppression.
Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models
Guo Z., et al. Oncotarget; 8(52): 89761–89774 (2017)
The article provides a suite of in vivo experiments showing that Axl inhibition via bemcentinib reprogrammes the immunological tumour microenvironment amongst others via increased proliferation and activation of CD4 and CD8. Bemcentinib and PD-1 blockade are also shown to act synergistically.
Bemcentinib mode of action & biomarkers
Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy
Kanzaki, R., et al., Scientific Reports; 7 (10613) (2017)
The tumor stroma microenvironment (TME) is comprised of cancer-associated fibroblasts (CAFs) which influence cancer cells such as non-small cell lung cancer (NSCLC). In a murine model, NSCLC treated with cisplatin induced an up-regulation of Gas6. The NSCLC line H1299 migrated in response to Gas6. The CAF cell line LCAFhert expresses GAS6 and can promote H1299 cell migration. In conclusion- CAF derived GAS6 promotes migration of Axl-expressing lung cancers.
Association of warfarin use with Lower overall cancer incidence among patients older than 50 years
Haaland, G.S., et al., JAMA Intern Med., 1;177(12):1774-1780 (2017)
Warfarin inhibits Axl signalling and Axl-mediated biological response at doses lower than those which mediate anti-coagulation effects. Retrospective analysis of a large population cohort demonstrates that patients on low dose Warfarin had a significantly lower incidence of cancer.
Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion-A New Role for the AXL Receptor Tyrosine Kinase
Aguilera, T.A. & Giaccia, A.J. Clin Cancer Res. 15;23(12):2928-2933 (2017)
Immune checkpoint inhibitors are most effective against T-cell inflamed tumours. Non-T-cell or T-cell excluded tumours remain a significant barrier to treatment. Axl identified as a key mediator of immune evasion and experimental evidence demonstrates Axl targeting leads to greater anti-tumour immune response post radiotherapy.
Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer
Miller, M.A., et al., Clin Cancer Res. 1;23(3):623-629 (2017)
Proteases known as sheddases cleave the extracellular domain of several receptor tyrosine kinases such as Axl generating soluble Axl (sAxl). Plasma levels of sAxl are predictive of patient response to standard of care BRAF & MEK inhibitor therapy and could be used for patient stratification strategies.
The GAS6-AXL signalling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer.
Antony et. al., Sci. Signal. Vol. 9, Issue 448, pp. ra97 (2016)
Axl co-clustered cMET, EGFR, and HER2, producing sustained extracellular signal-regulated kinase (ERK) activation in Mes cells. Bemcentinib reduced tumor growth in chick chorioallantoic membrane model.
AXL inhibition to overcome therapy resistance
Expression of tyrosine kinase receptor AXL is associated with worse outcome of metastatic renal cell carcinomas treated with sunitinib
Zucca, L.E., et al, Urol Oncology; 36(1): 11.e13–11.e21 (2017)
Renal cell carcinoma (RCC) represents 2-3% of all cancers in the Western world. First line therapy is sunitinib (PDGF/VEGF TK inhibitor). 47% of RCC patients treated with sunitinib were +ve for Axl. Axl expression in sunitinib treated patients correlated with worse clinical outcome (13 months Vs 43 months survival).
Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer
Husain, H., et al., (2017) Mol. Cancer Ther., 16(2):265-272 (2017)
Patient treated with EGFR based therapies develop resistance via multiple mechanisms. Resistant metastatic lung cancers exhibit increased AXL, EMT and PDL1 expression.
AXL Mediates Resistance to PI3Ka Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas
Elkabets et. al., Cancer Cell 13;27(4):533-46 (2015)
Axl mediates persistent mTOR activation and upregulated in resistant tumors. Combined treatment with PI3Ka and either EGFR, AXL, or PKC inhibitors reverts this resistance
A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial to mesenchymal transition
Mak et. al., Clin Cancer Res. 1;22(3):609-20 (2016)
EMT signature was developed based on 11 tumor types. Axl was frequently over expressed in EMT tumors along with PD-L1, PD1, CTLA4, OX40L, and PDL2. The article highlights the possibility of utilizing EMT status, independent of cancer type, as an additional selection tool to select patients who may benefit from immune checkpoint blockade.
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
Zhang et. al., Nat Genet. 1;44(8):852-60 (2013)
AXL biology reviews
A New Therapeutic Target in Lung Cancer
Levin, P.A., et al., J Thoracic Oncol 11(8): 1357-1362 (2016)
Axl belongs to the TAM family of receptor tyrosine kinases, which consists of Tyro3, Axl, and Mer. All three family members have similar structures and share a number of ligands, including the vitamin K–dependent ligands growth arrest protein 6 (Gas6) and protein S. In normal tissues, TAM receptor tyrosine kinases contribute to immune response regulation, including clearance of apoptotic cells and inhibition of cytotoxic immune activation in response to apoptosis. When cells undergo apoptosis, the polarity of the plasma membrane lipid bilayer is altered, externalizing the anionic phospholipid phosphatidylserine (PS). Gas6, which is often prebound to Axl, binds PS via the γ-carboxyglutamic domain. This ligand-dependent Axl activation regulates macrophage-mediated endocytosis and clearance of apoptotic cells by a process termed efferocytosis while inhibiting proinflammatory cytokine response.1 In preclinical models, TAM receptor triple-knockout mice (Tyro3-/-, Mer-/-, and Axl-/-) develop normally, but as the immune system matures, chronic inflammation and autoimmunity tends to develop. TAM receptor tyrosine kinases also participate in platelet activation and clot stability.2 Other less-studied mechanisms of Axl activation include ligand-independent homodimerization of Axl due to receptor overexpression, transcellular homophilic binding of the Axl extracellular domain, heterodimerization with other TAM family receptors such as Tyro3, and dimerization with non-TAM receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR).
Tumor Plasticity Interferes with Anti-Tumor Immunity
Chouaib et. al., (2014)
Since tumor cell plasticity was first shown to be crucial in tumor promotion and immune surveillance evasion, it has become an issue of intense investigation. Several mechanisms are associated with the acquisition of tumor cell plasticity and immune evasion, including loss of epithelial phenotype through epithelial-to-mesenchymal transition (EMT). We discuss recent evidence revealing that tumor cell plasticity may lead to the emergence of immunoresistant variants and how the tumor microenvironment evolves to shape this plasticity. We argue that targeting carcinoma cell plasticity represents a novel strategy to better control the emergence of resistant variants and to ensure more effective cancer therapies. In this context, the design of innovative integrative immunotherapy approaches is warranted.
Giving AXL the axe: targeting AXL in human malignancy
Gay et. al., Br J Cancer 14;116(4):415-423 (2017)
The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation.
Gene of the month: Axl
Brown et. al., BMJ Journals (2016)
The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research.
New twists in the AXL(e) of tumor progression. Science Signalling
Halmos et. al., Sci. Signal. Vol. 9, Issue 448, pp. fs14 (2016)
Patients with a mesenchymal subtype of ovarian cancer face a poor prognosis with limited treatment options to halt metastatic progression. In this issue of Science Signaling, Antony et al. found that the kinase AXL drives the mesenchymal gene signature and motility of ovarian tumor cells. AXL inhibitors may thus slow tumor progression in this subset of patients.