Our study reveals that tilvestamab's anti-cancer efficacy arises from superior kinetic stability in AXL binding and direct modulation of cellular biomechanics. By enhancing membrane rigidity, tilvestamab impairs cancer cell migration and proliferation-key drivers of metastasis. These findings provide the biomechanical rationale for tilvestamab's therapeutic activity, positioning it as a promising agent for targeting AXL-dependent cancers through mechanopharmacological mechanisms.

Our findings support the combination of batiraxcept and trastuzumab as a promising therapeutic strategy for aggressive HER2+ endometrial cancer.

P1, N=19, Active, not recruiting, University of Oklahoma | Trial completion date: Sep 2025 --> Feb 2026

TAM family kinase inhibitors significantly reduce the proliferation and colony formation of K562-S and K562-R cells by inducing apoptosis, interfering with Wnt/β catenin pathway, and upregulating cell cycle inhibitors.

The primary challenges ahead lie in delineating its molecular mechanisms of action beyond angiogenesis, prospectively defining resistance pathways to guide combination therapies, and rigorously evaluating its safety profile to ensure successful clinical translation. This letter outlines these priorities to stimulate further research.

Although these targeted therapies show potential to overcome resistance and improve patient outcomes, challenges remain due to the complex regulation of EMP. Future directions focus on refining combination strategies and advancing personalized approaches to enhance efficacy across multiple cancer types.

P1, N=83, Terminated, Incyte Corporation | Active, not recruiting --> Terminated; The study was terminated after careful review of the overall clinical activity of this compound and a lack of robust efficacy. The study closure is not based on safety concerns.

Glu2 near the N terminus of AXL is essential for binding. The data give a structural view into the AXL-tilvestamab complex and allow for further optimisation of the binding interface.

The novel anti-angiogenic inhibitor, KC1036, is effective in treating ES in the preclinical models.

P1, N=18, Not yet recruiting, Qurient Co., Ltd.

Furthermore, molecular dynamics simulation over 200 ns revealed stable protein-ligand complexes with some minor conformational fluctuations. This study suggests that, after further experimentation, modulating AXL with natural compounds holds promise for combating human malignancies, potentially overcoming limitations of existing synthetic inhibitors such as R428.

Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.