Mesothelioma Cells Rewire Genes to Resist New Drug
Research & Clinical Trials
Written by Sean Marchese | Edited by Amy Edel
Mesothelioma cells have a survival trick. When researchers exposed them to an experimental drug that targeted one of the cancer’s main growth switches, the cells didn’t die. Instead, they found a way around the drug’s effect.
A new study in the journal Nature Structural & Molecular Biology has uncovered the trick cancer cells use to evade the drug’s effects. The study finds that cancer cells change how their genes are turned on and off, finding a way around the drug’s effect.
Key Facts
- Researchers studied cells from mesothelioma patients with 2 gene mutations: NF2 and LATS2.
- An experimental drug called GNE-7883 blocks the TEAD protein, a growth switch present in most mesothelioma tumors.
- The cancer cells eventually found a way around this drug, changing how they read their genetic code.
- A gene called KLF4 was responsible for this change. When it was turned off, the cancer cells slowed their growth.
Though the discovery doesn’t impact the treatment of mesothelioma patients today, it does provide researchers with a map of the cancer’s way around the drug. And it potentially offers a way to stop that escape route in the future.
Why This Growth Switch Matters in Mesothelioma
Every cell has built-in brakes that prevent it from growing out of control. In many mesothelioma tumors, two of those genetic brakes fail: genes called NF2 and LATS2.
When the brakes fail, it causes the protein YAP to increase and bind to the protein TEAD, activating the genes that make the cell grow. If TEAD is the switch, YAP is responsible for flipping it.
Because of its vital role in the uncontrolled growth of mesothelioma cells, TEAD-blocking drugs have become one of the most closely watched developments in mesothelioma research. If the switch can be blocked, the cell should no longer be able to grow.
How the Cancer Cells Fought Back
Researchers treated the mesothelioma cells with the TEAD-blocking drug. At first, it worked. The switch turned off, and the cancer cells slowed down. But then the researchers increased the dose very slowly over about 2 months. Some of the cancer cells survived, and they continued to grow.
Genes have what is essentially an “on switch,” or promoter, and another switch located farther from the gene’s DNA, known as an enhancer. In the cancer cells that survived the higher drug dose, the enhancer failed to switch on.
The cells adapted to the lack of that enhancer, learning to directly operate the on switch for the gene’s promoter without needing the helper switch at all. Researchers dubbed this process “promoter reinforcement.”
The Gene Behind the Resistance
One of the genes that stood out as important for this workaround was KLF4. In resistant cells, KLF4 became more active at the on-switches of several cancer-driving genes.
If KLF4 was turned off in resistant cells, those cells lost their shortcut to rapid growth. The growth of those cells slowed dramatically. Cells that had never been exposed to the drug didn’t experience any effect from turning off KLF4.
This discovery makes KLF4 a promising drug target. A drug that inhibited both the growth of the cancer cells and this workaround would be more effective.
What Patients Should Know
Since GNE-7883 isn’t available outside of a research lab yet and the drug is still being studied, it’s not approved for use in treating mesothelioma. However, the Nature Structural & Molecular Biology study has helped to explain why certain drugs work for treating mesothelioma at the beginning of treatment but eventually fail as the cancer adapts to the drug. Now, scientists understand how to prevent that adaptation from occurring.
Patients with NF2 and LATS2 gene mutations, or those interested in the latest research on mesothelioma treatment, can find out whether they may be eligible to participate in any clinical trials related to this growth switch. By studying the genetics of mesothelioma, scientists can determine which treatments will be available to patients in the future.
