Publications
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.
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.
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.
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.
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.
Scientific presentations
ASCO 2022, Bhalla et al.
Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC
ASH 2021, Sonja Loges et al.
13th December 2021
Bemcentinib (Oral AXL Inhibitor) in combination with Low-dose Cytarabine Is Well Tolerated and Efficacious in Older Relapsed AML Patients. Updates from the Ongoing Phase II Trial (NCT02488408) and Preliminary Translational Results indicating Bemcentinib elicits anti-AML immune responses.
SITC 2021, Rolf A. Brekken et al.
9th November 2021
AXL targeting with bemcentinib restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through innate immune cell mediated expansion of TCF1+ CD8 T cells
ASV 2021, Mr. Dana Bohan
20th July 2021
Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Agent for COVID-19
Non-Small Cell Lung Cancer Drug Development Summit 2021, Prof. Hani Gabra
15th July 2021
Reprogramming of the Lung Cancer Tumor Microenvironment With the AXL Inhibitor Bemcentinib
ECCMID 2021, Akil Jackson
12th July 2021
Bemcentinib, an oral AXL kinase inhibitor, results in lower mortality compared to standard of care (steroids with or without remdesivir) in hospitalised patients with COVID-19
EAU 2021, Tony J. Chen
10th July 2021
Successful therapy of experimental, orthotopic renal cell carcinoma with two different types of AXL-inhibiting agents
4th Annual Next Gen Immuno-Oncology Congress, Prof. Hani Gabra
1st July 2021
The role of AXL in immuno-oncology: A translational perspective
EHA 2021, Dr. Sonja Loges et al.
11 June 2021
The combination of AXL inhibitor bemcentinib and low-dose cytarabine is well tolerated and efficacious in elderly relapsed AML patients: Update from the ongoing BGBC003 Phase II trial (NCT02488408)
ERA-EDTA 2021, Linn Hodneland Nilsson
6 June 2021
Tilvestamab, a function-blocking monoclonal antibody inhibitor of AXL RTK signalling, limits the onset of renal fibrotic changes in human kidneys ex vivo
ASCO 2021, Lauren Byers et al.
4 June 2021
Ph I/II study of oral selective AXL inhibitor bemcentinib (BGB324) in combination with erlotinib in patients with EGFRm NSCLC: End of trial update
Virtual Immunology 2021, Dana Bohan et al.
10 May 2021
Phosphatidylserine Receptors Enhancement of SARS-CoV-2 Entry: AXL as a Therapeutic Target for COVID-19
CROI 2021, Wendy Maury et al.
6 March 2021
Targeting of the Receptor Tyrosine Kinase AXL by Bemcentinib prevents SARS-CoV-2 infection
ASH 2020, Prof. Sonja Loges et al.
6 December 2020
The combination of AXL inhibitor bemcentinib and low dose cytarabine is well tolerated and efficacious in elderly relapsed AML patients: an update from the ongoing BGBC003 Phase II Trial
ASH 2020, Prof. Uwe Platzbecker et al.
5 December 2020
Efficacy and safety of bemcentinib in patients with Myelodysplastic Syndromes or Acute Myeloid Leukemia failing Hypomethylating Agents
SITC 2020, Professor James Spicer, PhD, FRCP
11 November 2020
A PhII study of bemcentinib, a first-in-class selective AXL kinase inhibitor, in combination with pembrolizumab, in pts with previouslytreated advanced NSCLC: Updated clinical & translational analysis
ASH 2019, Sonja Loges et al
9 December 2019, Orlando, USA
Durable responses observed in elderly AML patients ufit for intencive chemotherapy with First-in-Class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC: Phase II open-label study.
SITC 2019, Matthew Krebs et al
8 November 2019, Maryland, USA
Oral presentation in High Impact Clinical Trials:
A phase II study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC: Updated analysis
ESMO 2019, Oddbjørn Straume et al
30 September 2019, Barcelona, Spain
Poster Presentation:
Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
ESMO 2019, Jose M. Trigo Perez et al
28 September 2019, Barcelona, Spain
Poster Presentation:
Preliminary efficacy results of selective AXL inhibitor bemcentinib with pembrolizumab following chemo in patients with NSCLC
CICON 2019, Kjersti T. Davidsen et al
27 September 2019, Paris, France
Poster presentation:
AXL Inhibition Improves Immunotherapy by Targeting Local and Systemic Tumor Myeloid Cross-Talk
WCLC 2019, Felip et al
07 – 10 September 2019, Barcelona, Spain
Mini-oral Presentation:
Efficacy Results of Selective AXL Inhibitor Bemcentinib with Pembrolizumab Following Chemotherapy in Patients with NSCLC
WCLC 2019, Krebs et al
07 – 10 September 2019, Barcelona, Spain
Poster Presentation:
A Phase II Study of Selective AXL Inhibitor Bemcentinib and Pembrolizumab in Patients with NSCLC Refractory to Anti-PD(L)1
EHA 24, Hellesøy et al
June 13 - 16 2019, Amsterdam, Netherlands
Poster Presentation:
Single Cell Signaling Pharmacodynamics in a Phase 1b Clinical Trial of the AXL inhibitor bemcentinib in Acute Myeloid Leukemia and Myelodysplastic Syndrome
EHA 24, Loges at al
June 13 - 16 2019, Amsterdam, Netherlands
Poster Presentation:
The Combination of bemcentinib, a novel, oral, selective AXL-Inhibitor and Low-Dose Cytarabine yields Durable Responses in AML patients Unfit for Intensive Chemotherapy
ASCO 2019, Loges et al
May 31 - Jun 4 2018: Chicago, IL
Poster Presentation:
First-in-class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC or decitabine exerts anti-leukaemic activity in AML patients unfit for intensive chemotherapy: a Phase II open-label study
ASCO 2019, Felip et al
May 31 - Jun 4 2018: Chicago, IL
Poster Presentation:
A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in patients with advanced NSCLC: OS for stage I and preliminary stage II efficacy.
CCBIO, Blø et al
May 13 - 14, 2019: Bergen, Norway
Poster Presentation:
BGB149, a novel clinical stage humanised anti-AXL function blocking antibody
AACR, Ramkumar et al
Mar 29 - Apr 3, 2019: Atlanta, Georgia
Poster presentation:
Targeting AXL sensitizes non-small cell lung cancer to ATR inhibitors by enhancing replication stress
AACR, Chouaib et al
Mar 29 - Apr 3, 2019: Atlanta, Georgia
Poster presentation:
AXL targeting enhances lymphocyte-mediated cytotoxicity of lung cancer cells
AACR, Du et al
Mar 29 - Apr 3, 2019: Atlanta, Georgia
Poster presentation:
AXL is critical for pancreatic cancer progression and metastasis
60th American Society of Hematology Meeting (ASH)
Dec 1 - 4 2018: San Diego
Poster presentation by Loges et al:
Comprehensive Analysis of the Dose Escalation, Expansion and Correlates in the Ph I/II Trial BGBC003 with the Selective Oral AXL Inhibitor Bemcentinib (BGB324) in Relapsed/Refractory AML and MDS
SITC, Krebs et al
Nov 7 - 11 2018: Washington DC
Late breaking abstract poster presentation:
A Phase II study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC: Analysis of the first stage
SITC, Holt et al
Nov 7 - 11 2018: Washington DC
Poster presentation: Predictive and pharmacodynamic biomarkers associated with treatment with the oral selective AXL Inhibitor bemcentinib in combination with pembrolizumab in patients with advanced NSCLC and Melanoma
ESMO, Holt et al
Oct 19 - 23 2018: Munich, Germany
Poster Discussion: Predictive and Pharmacodynamic Biomarkers Associated with Phase II, selective and orally bioavailable AXL Inhibitor Bemcentinib Across Multiple Clinical Trials
ESMO, Schuster et al
Oct 19 - 23 2018: Munich, Germany
Poster Presentation: Update on the randomised Phase Ib/II study of the selective small molecule AXL inhibitor bemcentinib (BGB324) in combination with either dabrafenib/trametinib or pembrolizumab in patients with metastatic melanoma
ESMO, Medyouf et al
Oct 19 - 23 2018: Munich, Germany
Poster Discussion: The identification of the AXL/Gas6 signalling axis as a key player of myelodysplastic syndrome (MDS) and the potential of the oral selective AXL inhibitor bemcentinib in the treatment of MDS
23rd Congress of the European Hematology Association (EHA)
Jun 14 - 17 2018, Stockholm, Sweden
Poster presentation by Loges et al.
BerGenBio ASCO 2018 reception
The reception, which coincided with the annual American Society of Clinical Oncology (ASCO) meeting, provided stakeholders, including clinicians, investors, analysts and media, with interim data from the ongoing clinical trials of bemcentinib alone and in combination with standard of care drugs in multiple cancer indications. Presentations were made by key opinion leaders, clinical trial principle investigators and members of the BerGenBio team.