New project funded by Breast Cancer Now!
We are grateful and excited to announce that we have just received funding from Breast Cancer Now to work on understanding innate immune responses associated with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. Mutations in these genes are thought to be causative in about 6% of breast cancer cases, and these mutations have also been associated with other cancers such as ovarian or lung.
One of the consequences of mutation of BRCA1 or BRCA2 is that cancer cells cannot maintain accurate copies of their genetic material, DNA. They also become defective in properly repairing damage that can occur to DNA. Although these defects can drive cancer formation and development, they are also an Achilles heel for these cancers. This is because a special class of drugs used to treat cancer, known as PARP inhibitors (PARPi for short) can be used to selectively kill cancer cells with mutations in BRCA1 or BRCA2. However, the use of these drugs to treat patients has shown that not all patients’ tumours respond to them, and that even if tumours initially respond and shrink, resistant cells can arise by picking up additional mutations that make them insensitive to PARPi. It is therefore imperative to develop ways that allow PARPi to work faster and more effectively.
Over the last few years, it has become more and more apparent that activating the immune system to detect and attack tumours is an essential contributor to successful cancer therapy with PARPi. However, how to boost these responses is not very well understood. As it turns out, many of the ways the body fights against bacterial and viral infections can also be repurposed to fight against cancer cells. One of these is the cGAS pathway, which our lab studies extensively. This pathway is normally activated upon the detection of the DNA of pathogens, which forms their genetic material just like it does in our own cells, as well as in cancer cells. Normally, the cGAS pathway only responds to viral and bacterial DNA. However, during treatment with PARPi, a cancer cell’s own DNA can trigger cGAS, and can activate anti-tumour immune responses.
In this project, we will investigate how BRCA1/2 mutations trigger cGAS activation, and how this is modulated upon PARPi treatment, and how it is changed in cells that have acquired resistance to these drugs. In addition, we will identify genetic regulators of cGAS activation, which we hope will pinpoint co-treatment options. Ultimately, we hope that this project will improve the effectiveness of PARPi by helping them work faster, with fewer side-effects, and to lead to a lower rate of tumour resistance.