bemcentinib (BGB324)

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.

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.

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.

Combination therapy using either lenvatinib or sorafenib and selective CAV1 inhibitors (e.g., siCAV1/miR-7), or AXL/FGFR4 inhibitors (e.g., BGB324/BLU9931) effectively overcame pan-TKI resistance. Our findings highlight a previously unrecognized role for CAV1-driven signalling in sustaining tumour dormancy, a critical and challenging therapeutic barrier underlying recurrence and pan-TKI resistance in HCC. Therapeutically targeting these pathways offer a promising and novel strategy to eliminate dormant tumour cells, thereby overcoming resistance and improving treatment outcomes.

Preclinical studies highlight the efficacy of Axl inhibitors, such as bemcentinib, brigatinib, and enapotamab vedotin, in overcoming drug resistance and enhancing immune responses. Clinical trials combining Axl inhibitors with ICIs (e.g., pembrolizumab) show promise, particularly in STK11-mutant NSCLC, with manageable toxicity profiles. However, challenges persist in optimizing dosing, managing adverse events, and identifying predictive biomarkers. Ongoing research into combination strategies and biomarker-driven approaches aims to refine Axl-targeted therapies and improve outcomes for patients with advanced NSCLC.

Moreover, targeting AXL with R428 significantly suppressed the self-renewal ability of CSCs and increased their sensitivity to Osimertinib. Taken these together, our study provides new insight into the role and mechanism of AXL in regulating NSCLC CSCs stemness. Our study also gives a new hint for the relationship between AXL and SCD1.

We found that treatment with the Axl-specific small molecule inhibitor bemcentinib yields increased expression of markers of activation in both macrophages and dendritic cells...Most importantly, we found that treatment-naïve tumor cells and targeted therapy-treated tumor cells have distinct impacts on macrophage state, and these differences dictate the nature of the immune cell response to Axl inhibition. As a whole, our work highlights the utility of in vitro models in unraveling the complex mechanistic effects of Axl inhibition and establishes a robust model system that can be used in future mechanistic drug studies with the potential to inform clinical trial design.

P1/2, N=26, Terminated, BerGenBio ASA | N=64 --> 26 | Trial completion date: Jul 2029 --> Apr 2025 | Recruiting --> Terminated | Trial primary completion date: Jul 2027 --> Jan 2025; Lack of efficacy

We first validated the expression of AXL in lymphatic endothelial cells (LECs), followed by functional studies using RNA interference and pharmacological inhibition with R428/Bemcentinib...Collectively, our findings pinpoint AXL as a potent enhancer of lymphangiogenesis operating through the VEGF-C/AKT pathway. Furthermore, the identification of AXL expression within a distinct LEC subpopulation, particularly in the context of metastasis, underscores the intricate interplay between AXL signaling and lymphatic dynamics within the lymph node microenvironment.

P1/2, N=44, Recruiting, The University of Texas Health Science Center at San Antonio | Not yet recruiting --> Recruiting

Estrogen receptor (ER)-positive breast cancer accounts for a substantial proportion of breast cancer cases and is typically managed using ER inhibitors, such as tamoxifen and fulvestrant. Interestingly, AXL knockdown did not enhance the sensitivity to 4-OHT or affect S6K1 signaling in either MCF7 or MCF7-TR cells, suggesting that the sensitizing effect of bemcentinib through S6K1 inhibition may be independent of AXL expression. Our findings suggest that bemcentinib treatment, particularly in combination therapy, could be a promising strategy for improving treatment efficacy and overcoming tamoxifen resistance in ER-positive breast cancer.

P1/2, N=64, Recruiting, BerGenBio ASA | Phase classification: P1b/2a --> P1/2 | Trial completion date: Aug 2025 --> Jul 2029 | Trial primary completion date: Aug 2025 --> Jul 2027