How Does Mesothelioma Become Resistant to Chemotherapy?
June 21, 2018
Scientists have developed many treatments for cancer, but this type of disease is rarely ever cured. One of the fundamental problems in cancer treatment is chemotherapy resistance.
Mesothelioma is an infamously drug-resistant form of cancer. There is only one chemotherapy regimen for mesothelioma approved by the U.S. Food and Drug Administration.
Sometimes, tumors don’t respond to chemotherapy at all. In other cases, chemotherapy controls tumor growth temporarily but eventually stops working.
Even in the best-case scenario where mesothelioma is sent into remission, the cancer usually reappears months or years later. When cancer recurs, it’s often immune to the drug that stopped it before.
Drug resistance is a problem in all areas of medicine. Researchers must constantly develop new antibiotics and vaccines to keep up with the evolution of bacteria and viruses.
Unfortunately, cancer cells also evolve defenses against the drugs doctors use against them. Researchers are searching for ways to overcome and reverse chemotherapy resistance.
How Chemotherapy Attacks Cancer Cells
Chemotherapy uses drugs that are toxic to human cells. The toxic damage causes cells to self-destruct or stop reproducing. Chemotherapy primarily affects cancer cells, but it also harms certain healthy cells.
This collateral damage causes side effects and limits the dosage doctors can safely prescribe.
Specific chemotherapy drugs damage cells in different ways. For example, the drug cisplatin is made out of a molecule that binds to DNA. Cisplatin is one of the standard chemotherapy drugs used in mesothelioma treatment.
When a cell’s DNA has cisplatin stuck to it, the cell can’t follow the DNA’s instructions for making the proteins the cell needs to function. The cell can’t make new copies of its DNA either.
Why Chemotherapy Stops Working
All cells have natural ways to protect themselves from toxins. Cancer cells can use these mechanisms to resist the effects of chemotherapy. Some cancer cells start out with these mechanisms switched on, while other cancer cells adapt in response to drugs.
Chemotherapy drug resistance can be intrinsic or acquired:
Intrinsic resistance means a cancer cell is resistant from the start. If chemotherapy kills all the nonresistant cells in a tumor, the resistant cells will survive and reproduce. Then the tumor will grow back fully resistant. Resistant cancer stem cells can also create completely new tumors.
Acquired resistance means a cancer cell modifies itself to deal with a drug. If the drug dosage is not strong enough to kill cancer cells quickly, the cancer will have time to adapt and become immune. Eventually this can also lead to a tumor becoming fully resistant.
In particular, mesothelioma cells can evolve several ways of protecting themselves from cisplatin, including:
Reduced Uptake: Transforming their cell membranes to stop cisplatin from getting into the cell.
Increased Efflux: Modifying their cell membranes to pump cisplatin out of the cell.
Increased DNA Repair: Switching on extra mechanisms to repair damage caused by cisplatin.
Hypermethylation: Adding molecules to their DNA that stop cisplatin from bonding with it.
Searching for Ways to Overcome Drug Resistance
There are two challenges in overcoming chemotherapy resistance: Finding the weakness of cancer cells with intrinsic resistance and disabling or destroying those cells before they can acquire resistance.
Combining different drugs helps target cells with different natural resistances, and combining different treatments gives cancer cells fewer ways to survive.
For example, standard chemotherapy for mesothelioma combines cisplatin with pemetrexed (Alimta). This regimen is then often combined with surgery, radiation therapy, immunotherapy or other treatments.
Doctors also look for ways to make chemotherapy less toxic for patients. If the collateral damage to healthy cells can be reduced, the drug dosage can be safely increased. A higher dosage will kill cancer cells faster and more completely.
Delivering chemotherapy directly to the site of the cancer is one way to spare healthy cells.
Hyperthermic intraperitoneal chemotherapy (HIPEC) is an established method for peritoneal mesothelioma.
For pleural mesothelioma, doctors are testing a similar method called hyperthermic intrathoracic chemotherapy (HITHOC).
Researchers are also studying the cellular mechanisms that cause chemotherapy resistance. Their hope is to develop ways to counteract these mechanisms and re-sensitize cells to chemotherapy.