AXL receptor in bladder cancer: on the crossroad between mechanotransduction and RTK signalling

Collaborative Research Program for 2025-2027

Muscle Invasive Bladder Cancer (MIBC) is the most common cancer of the urinary tract with a poor prognosis. The disease affects primarily elderly people, and therefore, the incidence rates of MIBC are increasing in countries with ageing populations, such as Kazakhstan. Moreover, MIBC is the most expensive cancer to treat, and the recommended international guidelines for the management of MIBC have remained unchanged for decades. Therefore, developing novel treatment schemes for MIBC is considered an unmet need in oncology.
Literature data and our unpublished results suggest that the molecular pathway activated by the Receptor Tyrosine Kinase (RTK) AXL and its ligand GAS6 is a promising therapeutic target in MIBC. Indeed, the difference in the median survival of the patients with AXL-positive and AXL-negative tumours is drastic (roughly 25 vs 57 months). In normal physiological conditions, AXL is present in professional phagocytes, such as dendritic cells, where it is implicated in the clearance of apoptotic cells via a process of efferocytosis. In addition, AXL activates cell survival pathways to secure the survival of phagocytes operating in toxic environments. When hijacked by cancer cells, AXL activates cell migration and processes of epithelial-mesenchymal transition, likely by utilizing some elements of a pathway controlling efferocytosis in dendritic cells. Moreover, many cancer cells rely on AXL signalling to gain therapy resistance. Although the GAS6/AXL pathway has been explored as a potential target in several cancer types, detailed mechanistic studies of the role of AXL in drug resistance are largely missing.
We found that the micromolar concentrations of small molecule inhibitors of AXL show cytotoxicity in MIBC cells. Surprisingly, however, we found that prolonged exposure of BC cells to these inhibitors results in phosphorylation of AXL in the A-loop at Y702 and Y703, phosphorylation of EGFR at Y1068, and activation of MAPK signalling. Likewise, treatment with gemcitabine or cisplatin causes AXL Y702/Y703 phosphorylation. In addition, our preliminary data show that this phosphorylation is required for the accumulation of the mature receptor at the cell membrane. According to our preliminary data, AXL expression is under the control of a transcription factor complex YAP/TEAD that is, in turn, regulated by the rigidity of the extracellular matrix in the tumour microenvironment.
In this proposal, we plan to apply a mouse model of MIBC and patients-derived tumour organoid cultures to gain insight into the regulation and function of AXL in bladder cancer. The proposal aims to characterise molecular pathways leading to the activation of EGFR/MAPK signalling in MIBC cells in response to cytotoxic insults. We propose that their pharmacological inhibition or blocking of TEAD/YAP activity will potentiate the effect of AXL inhibitors and chemotherapeutics in BC. We anticipate that combination therapy approaches based on these findings will increase efficacy and reduce the cytotoxicity of the treatment in future clinical trials. As a part of the proposed study, we plan to optimise protocols for generating MIBC tumour organoids, which can decrease the cost and increase the reproducibility of this important technique.