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Speaker: Austin James Rayford, University of Bergen

Title: A conserved culprit: Targeting dual AXL-mediated mechanisms of immunotherapy resistance in lung cancer patients
Host:ÌýCarina Strell
Where:Ìý
When: January 30, 2025 at 14.30-15.30

No registration necessary.Ìý

Abstract:ÌýLung cancer is a leading cause of cancer-related morbidity and mortality worldwide, and is also responsible for most cancer-related deaths in Norway. Non-small cell lung cancer (NSCLC) accounts for around 80% of lung cancer cases. The introduction of targeted therapies and immune checkpoint inhibitors (ICIs) has revolutionized the treatment of NSCLC in recent years, particularly due to the remarkable clinical efficacy of ICIs observed in a subset of patients. However, innate and acquired resistance to ICIs remains a barrier to durable clinical benefit, and the complex molecular mechanisms mediating resistance are still poorly understood.Ìý

AXL, a receptor tyrosine kinase, is upregulated by normal and malignant cells in many tissues during chronic inflammation and wound-healing, and is also a central negative feedback regulator of innate immunity. Although many studies have implicated AXL in both tumor-intrinsic and immune-mediated mechanisms of ICI resistance, current data on AXL expression in tumor and immune cells in clinical NSCLC specimens is lacking, while its prognostic and predictive role in the context of ICI treatment and the ability of AXL-inhibiting drugs to potentiate ICI efficacy remains elusive.Ìý

In this work, we first showed that AXL expression in tumor cells was associated with aggressive phenotypic features, an immunosuppressive tumor microenvironment and poor survival in a real-world cohort of NSCLC patients treated with ICI monotherapy. We then demonstrated that the addition of bemcentinib, a selective small-molecule AXL inhibitor, to ICI therapy in a multi-national clinical trial of advanced pretreated NSCLC patients resulted in improved clinical benefit compared to standard-of-care treatments, particularly within subgroups with AXL-positive and STK11-inactivated tumors expected to have the worst prognosis. In murine models, bemcentinib sensitized STK11-mutant NSCLC tumors to ICI treatment via AXL-targeting in dendritic cells, suggesting an additional tumor-cell extrinsic mechanism that supports the efficacy of bemcentinib-ICI treatment observed in patients with STK11-loss. Taken together, these findings provide a strong scientific rationale for current and future clinical trials incorporating AXL inhibitors with ICI therapy to improve NSCLC patient outcomes.

Austin RayfordÌýreceived his BSc. in Chemical Biology in 2015 from the University of California, Berkeley. After working for 2 years at Roche Molecular Systems he moved to Bergen and completed his MSc. in Biomedical Sciences in Jim Lorens’ group. Austin began working for BerGenBio in 2019 in the Exploratory Biomarkers team and completed an industrial PhD project under Jim Lorens co-funded by BerGenBio and the Norwegian Research Council. As a current Researcher in the Lorens Lab and CCBIO, he continues to explore how AXL inhibitors can potentiate the efficacy of standard-of-care therapies in advanced NSCLC and melanoma patients.

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