Structure, mechanisms of regulation and targeting of oncogenic tyrosine fusion kinases in Leukaemia

Context Tyrosine kinases are a group of proteins that are essential for normal cellular function and growth. The function of these kinases is normally tightly controlled in the cell. Genetic mutations can lead to these tyrosine kinase genes becoming fused to fragments of other genes, resulting in ‘Tyrosine fusion kinase’ proteins. These fusion proteins which are found in haematological malignancies and solid tumours, instead drive uncontrolled growth of cancer cells. They subsequently serve as biomarkers and therapeutic targets for these cancers. BCR:ABL fusion proteins are found in almost all patients with Chronic Myeloid Leukaemia (CML) and around 25% of patients with Acute Lymphoblastic Leukaemia (Ph +ve ALL). BCR:ABL drives uncontrolled growth and survival of Leukaemia cells, as it bypasses normal signals that tell the cell to ‘switch off’ growth. Further BCR:ABL interacts with another important protein called the Heat Shock Protein 90 (HSP90), which is a ‘chaperone’ helping to stabilise these fusion proteins protecting them from being broken down and removed from the cancer cells. The challenge the project addresses Two different forms of BCR:ABL are found in CML and ALL (p210 and p190 respectively). There is potential in this project to understand how structural differences in these two forms of BCR:ABL impact the differences in function, disease progression and response to current treatments in patients with CML and ALL. This project addresses the challenge of a lack of understanding of the structural mechanisms by which these large fusion proteins assemble into their cancer-driving forms and are recruited to the HSP90 molecular chaperone complex for stability. This project further focuses on challenges of finding novel approaches to disrupting the function of BCR:ABL fusions, and their interactions with HSP90 in CML and ALL. Aims and objectives To visualise the three-dimensional structures of BCR:ABL fusion proteins in CML and ALL and observe how they are attached to the HSP90 chaperone protein, using a technique called Cryogenic Electron Microscopy (CryoEM). To identify and test new ways that BCR:ABL structure and interactions with HSP90 can be targeted to disrupt the function of these fusion kinases. To compare BCR:ABL interactions with the HSP90 chaperone in CML and ALL cancer cells, in patients who respond to current treatments and those who do not. Ultimately investigating approaches to using HSP90 inhibitors to disrupt these interactions. Potential Applications and Benefits Current therapies used to treat CML and ALL, largely focus on blocking BCR:ABL kinase activity with drugs called Tyrosine Kinase Inhibitors (TKIs). However these are not curative and patients often have to take these drugs life-long, experiencing disease relapse after the treatment is stopped, living with side effects of these treatments. Further mutations in the BCR:ABL proteins cause resistance to TKIs. The applications and benefits of this project are in identifying new approaches to block the function of BCR:ABL fusions in CML and ALL, paving the way for the potential development of new treatments, with the long-term impact of improving outcomes and quality of life for patients. Further understanding of fundamental biological processes underlying cancer progression driven by BCR:ABL fusion kinases, will also benefit research into other cancers, similarly driven by fusion kinases, that depend on the HSP90 chaperone for function, where patients also experience the limitations associated with current TKI treatments.