Discovery of Synthetic Lethal and Tumor Suppressor Paralog Pairs in the Human Genome
This week we profile a recent publication in Cell Reports from the laboratory of Dr. Alice Berger (pictured) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
The goal of our lab is to develop new strategies for cancer therapy, with a particular focus on lung cancer. We use genome-wide genomics and functional genomics approaches to identify promising new cancer drug targets. Ultimately we hope to translate our early-stage discoveries into better outcomes for lung cancer patients.
What is the significance of the findings in this publication?
For the past decade, scientists have performed genome-wide screens to identify important cancer genes – first with shRNA and in the past few years with CRISPR. However, we and others noticed that paralogs – duplicated genes – were underrepresented as hits in these screens.
We wondered if this absence was due to redundancy between the two genes – if so, knocking out duplicated genes in tandem should produce an effect and reveal the function of the genes. It turns out that paralogs constitute about two-thirds of genes in the human genome, so a large portion of genes might not be well characterized using the standard single-gene technology.
Phoebe and James (the two first authors) leveraged new technology we call pgPEN to delete genes in pairs, and in doing so revealed that many paralogs are in fact essential for cancer cell survival and growth. About 12% of the 2000 paralogs we characterized were essential when knocked out as a pair but would have been missed by traditional methods.
What are the next steps for this research?
There are two impactful ways we hope to use these results. The first is that we have identified many gene families that could have promise as cancer drug targets that we were previously blind to. We are now characterizing several of these in detail to determine which show the most promise to target in the future. In many cases, it is possible that cancer therapies could be designed that target both of the paralog family members simultaneously – this is the way many existing drugs work, such as CDK4/CDK6 inhibitors
The second is that we might be able to target a single paralog in cancer cells that have lost expression of its duplicated pair. Cancer cells are rife with chromosomal abnormalities and often lose expression or copies of genes. Since the loss of one paralog is often tolerated, we expect that many cancer cells have lost copies of these duplicated genes. If we now deliver a drug targeting the other paralog, cancer cells will be particularly sensitive to this drug, whereas the normal cells, that retain both genes, should be protected. We think this creates a “therapeutic window” that enables specifically targeting cancer cells while sparing the normal cells, resulting in better efficacy and less toxicity.
If you’d like us to mention your funding sources, please list them.
This work was funded in part by the Lung Cancer Research Foundation, the National Science Foundation, the National Institutes of Health, the Washington Research Foundation, the Prevent Cancer Foundation, a Stephen H. Petersdorf Lung Cancer Research Award, the Edward P. Evans Foundation, the Leukemia & Lymphoma Society, the Mark Foundation for Cancer Research, the Paul G. Allen Frontiers Group and the Department of Defense Breast Cancer Research Program.