FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

Healthy human cells employ many tricks to avoid becoming cancerous. For example, they produce proteins known as tumor suppressors, which sense if a cell shows early signs of cancer and instruct the cell to die. A gene known as TP53 produces one of the most important tumor suppressor proteins, and this gene is inactive or missing in many types of human cancer. Treating cancers that have completely lost the TP53 gene is particularly difficult. One way to develop new treatments for these conditions would be to target other proteins that these cancers need to survive; but these proteins first need to be identified. Fan et al. have now identified one such protein in human cancer cells lacking TP53. Searching databases of DNA sequences from human cancer cells revealed that those without the TP53 gene often also lose a neighboring gene called FXR2. Cancer cells survive without FXR2 because a similar gene, called FXR1, can compensate. Fan et al. therefore decided to experimentally lower the activity of the FXR1 gene and, as expected, cancer cells without TP53 and FXR2 stopped growing. Normal cells, on the other hand, were unaffected by the deletion of the FXR1 gene since FXR2 is still there. This phenomenon, in which cancer cells become vulnerable after the loss of certain genes but only because they have already lost important tumor suppressors, is called “collateral lethality”. Further experiments showed that the protein encoded by FXR1 coordinates with other proteins to activate genes that contribute to cell growth. These findings suggest new ways to treat human cancers that have lost TP53. For example, if scientists can find small molecules that inhibit the protein encoded by FXR1 and show that these molecules can block the growth of tumors lacking TP53 and FXR2, this could eventually lead to a new anticancer drug. However, like any new drug, these small molecule inhibitors would also need to be extensively tested before they could be taken into human clinical trials.