Measuring susceptibility of cancer cells to BH3-mimetics

Measuring susceptibility of cancer cells to BH3-mimetics

Project details

BH3-mimetics are a new class of small molecule anti-cancer agents that specifically bind BCL2 prosurvival proteins such as BCL2 and MCL1 (Blombery, Cancer Discov. 2019 9(3):342). They are highly active in certain blood cancers including chronic lymphocytic leukaemia (CLL) and acute myeloid leukemia (AML). Nevertheless, despite the presence of the prosurvival target protein, many cancers are resistant to these agents, highlighting the need to clarify the mechanisms of sensitivity and resistance. 

This project aims to measure the BCL2 protein complexes that sensitise cells to BH3-mimetics, as well as those that cause resistance. Our current library of antibodies to the BCL2 protein family will be expanded to include antibodies specific for the complexes that form between BCL2 family members. The antibodies will be used in single cell methods (e.g. flow cytometry) to test whether the type and abundance of particular complexes help predict sensitivity to BH3 mimetics in cancer cell lines, prior to testing in samples from cancer patients.  

This project will involve screening of new antibodies to identify those specific for each protein complex, and then the use of those antibodies in flow cytometry to identify complexes in cells treated with BH3 mimetics to BCL2, MCL1 and BCLXL.  

About our research group

The Kluck lab investigates how cells die via a process called apoptosis - a normal process that helps remove excess or damaged cells. When apoptotic cell death goes wrong, the results are often cancer or autoimmune diseases.  

We are interested in the proteins inside cells that orchestrate apoptosis, in particular how two pore-forming BCL-2 family members, BAX and BAK, undergo a major conformation change to generate homo-oligomers that generate pores in the mitochondrial outer membrane.  

The overall goal of our research is to identify new means of specifically regulating apoptotic cell death in cancer and other diseases. 

 

Email supervisors

 

Researchers:

Dr Sweta Iyer in the lab
Dr
Sweta
Iyer
Blood Cells and Blood Cancer division

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