Role of TAM receptors in therapy resistance in bladder cancer

Faculty Development Competitive Research Grants Program for 2026-2028

Muscle-invasive bladder Cancer (MIBC) is a prevalent cancer of the urinary tract associated with a poor prognosis. The disease primarily affects elderly people, and therefore, the incidence rates of MIBC are increasing in countries with ageing populations, such as Kazakhstan. Additionally, MIBC is the most expensive cancer to treat, and the recommended international guidelines for the management of MIBC remained mostly unchanged for decades. Therefore, the development of novel treatment schemes in MIBC is considered an unmet need in oncology, both globally and specifically in Kazakhstan.
The current proposal focuses on the family of receptor tyrosine kinases known as TAM receptors (TYRO3, AXL, MER). In normal physiological conditions, they function in professional phagocytes as receptors facilitating efferocytosis, a process of clearance of apoptotic cells. In addition, TAM receptors activate cell survival pathways to secure the survival of macrophages and dendritic cells operating in a toxic environment. When hijacked by cancer cells, TAM receptors contribute to cell migration and processes of epithelial-mesenchymal transition. This likely involves some elements of a pathway executing efferocytosis in professional phagocytes. Moreover, many cancer types rely on TAM receptor signalling to gain therapy resistance, likely by employing mechanisms that ensure phagocyte survival. Specifically, TAM-dependent survival pathways lead to resistance to chemo-, radio-, and immunotherapy in breast, ovarian, and skin cancer.
Although the role of individual TAM receptors is insufficiently studied in MIBC, the data from the literature and public databases indicate their significance. For instance, AXL expression has been linked to the most aggressive molecular subtypes of MIBC. Notably, there is a significant difference in median survival between patients with AXL-positive and those with AXL-negative tumours, with survival times averaging 25 months and 57 months, respectively.
The aims of the current proposal include the characterization of the impacts of individual TAM receptors on MIBC drug resistance and the identification of the most effective commercial TAM inhibitors. Furthermore, the proposal aims to discover potential biomarkers that can predict tumour response to TAM-targeted therapy.
The current proposal benefits from the utilization of preliminary data generated in the labs of the PI and co-PI. The study is unique in its field because it utilizes previously developed MIBC cell models with individual, double, and triple knockout genes coding for TAM receptors. The novelty of this study also includes the comparison of urine proteomes with proteins detectable in matching PDO conditioned media. This dual approach will help identify the tumour cell secretomes, ultimately aiding in discovering biomarkers to assess tumour responses to chemotherapy and TAM-targeted therapies.