DHHC enzymes modify nearly 1,000 human proteins, including EGFRs, a family of receptors that are implicated in a range of cancers. These enzymes, also known as palmitoyltransferases, modify proteins by attaching to fatty acids of differing lengths in a process that can lead to changes in protein structure, function or location inside a cell. National Institutes of Health (NIH) scientists figured that if they could decode these enzymes, they could generate insights that might improve drug design for many types of cancer.
The team, from the NIH's National Institute of Child Health and Human Development, modeled the 3D structure of the human DHHC20 enzyme. In a process called palmitoylation, this enzyme modifies EGFR, which is over-activated in colon and non-small cell lung cancers. HER2, a type of EGFR, is over-expressed in an aggressive type of breast cancer. The work is published in Science.
Inhibiting DHHC activity to boost first-line treatments for breast and lung cancer is not a new idea, but there are no approved drugs aimed at specific DHHC enzymes. Decoding the structure of these enzymes now makes targeting them possible.
“Our study offers a starting point for developing DHHC20 inhibitors that may aid in treatment of common cancers and advance the field of protein palmitoylation,” said lead author Anirban Banerjee, Ph.D., head of NICHD's unit on structural and chemical biology of membrane proteins.
Several EGFR inhibitors are already on the market, including AstraZeneca’s Iressa and Genentech’s Tarceva, but some cancers can develop resistance to this class of drugs. Norway-based BerGenBio is working on reversing and preventing resistance by following an EGFR blocker with an AXL inhibitor.
Other teams are testing combinations in an effort to bolster standard treatments for aggressive breast cancer. For example, researchers in Ottawa, Ontario, tested a combination of oncolytic viruses, which identify a tumor to the immune system, along with a checkpoint inhibitor. The combination prevented relapse in more than 60% of mouse models of triple-negative breast cancer. The virus alone was half as effective, and the checkpoint inhibitor alone had no effect.
While modeling DHHC20, the NIH researchers identified a "cavity" that can be altered in size by mutations, thereby changing the palmitoylation process. That may shed light on how different enzymes work together to influence states of health and disease, they said in a statement.