Harnessing p53 to target CDK4/6 inhibitors resistant breast cancer

Project description

Breast cancer is the most common cancer among women in Australia, with over 21,000 new cases each year. About 70% of people with breast cancer have Estrogen Receptor Positive (ER+) cancer that responds to endocrine treatment. However, for about 30% of these people, the cancer eventually stops responding to treatment and spreads (metastasizes). Inhibitors of Cyclin-Ddependant Kinases 4 and 6 (CDK4/6i) are now standard of care treatment of metastatic ER+ breast cancer. However, treatment failure can develop and there are no effective second-line treatment strategies.

The work of Dr Achinger-Kawecka (The University of Adelaide) and others suggest that resistance to CDK4/6i may be caused by “jumping genes” – also known as Transposable Elements (TEs). These are pieces of ancient viral DNA that currently make up nearly half of our genome. Once thought to be inactive, TEs are now understood to play an important role in cancer by switching on genes that help tumours grow and resist treatment.

Dr Joanna Achinger-Kawecka and colleagues have also shown that activating a key tumour suppressor protein known asp53, could be a promising avenue for overcoming resistance to CDK4/6 inhibition. In this NBCF-funded study they will use preclinical models derived from tumour samples of ER+ patients who relapsed on CDK4/6i therapy to provide evidence that p53 activating drugs can turn off these oncogenic jumping genes and restore treatment sensitivity to CDK4/6i therapy.

Why is this work needed

Metastasis—the spread of cancer around the body—is responsible for all breast cancer deaths. About 30% of ER+ breast cancer cases progress to metastatic disease, largely due to resistance to CDK4/6i, the standard –of care treatment. Currently, no clear second-line treatment strategy is available for patients who develop resistance to CDK4/6i. As a result, the growing prevalence of CDK4/6 inhibitor resistance is set to become a significant challenge in managing metastatic ER+ breast cancer.

Expected outcomes

Outcomes from this study will elucidate the exact molecular mechanism of CDK4/6i resistance, focusing on the role of transposable elements. This study will provide pre-clinical evidence that drugs restore the activity of the tumour suppressor p53 can restore treatment sensitivity to CDK4/6i therapy, ultimately prolonging the time that people can benefit from their current therapy.