The Story of MAPK1 and ERK 1/2
Listen up: sometimes the uncontrolled growth that is cancer is also a communication fail.
Cancer is a disease of uncontrolled growth, but it’s also a failure of communication. Multicellular beings like us depend on cells that talk to each other. It’s how cells and organs work together and respect each other’s boundaries. Cancer’s communication breakdown often involves a gene called mitogen-activated protein kinase 1 or MAPK1 for short. In one out of every three human cancers, MAPK1 and its gang, well, they aren’t exactly listening.
It’s not necessarily MAPK1 or what is called an extracellular signal-related kinase (ERK1/2) – the protein MAPK1 codes for — that’s to blame. Often, the ERK1/2 protein only does what it’s told. The kinase is the last in a chain of intracellular components, a pathway of molecular players that work together to relay growth signals from outside of cells into the central command center or nucleus. As in a game of telephone whispered among children, those messages delivered within cells can be mangled. Sometimes they multiply like the worst, most persistent sort of emailed spam.
With no spam filter in place, each “ping” turns ERK1/2 on, to do exactly as those enzymes were designed to do. They set the machinery that controls cells’ growth and proliferation and other essential processes in motion. When those signals keep coming, cells have no way to turn off the MAPK1 pathway or their own frantic division. And that uncontrolled growth is cancer.
Sometimes, MAPK1 itself is at fault. For instance, changes to the MAPK1 gene recently turned up in the cancerous cells of children with a form of leukemia called hypodiploid acute lymphoblastic leukemia or ALL. A comprehensive search for mutations associated with another leukemia, chronic lymphocytic leukemia (CLL) uncovered several new altered genes underlying instances of that more common blood cancer, MAPK1 among them. An international team of researchers has unearthed a novel and recurrent mutation in the MAPK1 gene in some cases of cervical cancer too.
But the trouble MAPK1 can cause often starts somewhere farther up the chain. Mutations in upstream components of the pathway – namely the gene family called RAS and the gene BRAF – are frequently found in cancers of the skin, pancreas, thyroid, and more.
Some versions of MAPK-related genes may influence our predisposition to certain cancers, as researchers studying families affected by colorectal cancer have found. Using three different tools, they determined that genetic variants more often uncovered in people with cancer included an “overrepresentation of genes related to MAPK signaling pathways.” The risk for colorectal cancer went up as the number of MAPK-related risk variants in a person’s genome grew.
When it comes to MAPK, many paths can push toward the same basic problem: Cell growth gone rogue. But it’s not always as simple as the gene variants you or your tumor carries. The MAPK pathway is built to respond to outside signals after all, and can be influenced in complicated ways by the things us multicellular humans expose ourselves to, including nutrients, viral infections, and carcinogens.
For example, researchers have found associations between genes in the MAPK pathway and the dietary habits of people diagnosed with colon and rectal cancers, for better or worse. A diet high in fat may increase cancer risk for some people, depending on which particular version of the MAPK1 gene they carry. Evidence suggests that cruciferous veggies – a group including cabbage, broccoli and Brussels sprouts – may ward off cancers, by dampening the MAPK1 signal. (As an interesting aside, a chemical ingredient in broccoli can protect kidneys against the damaging effects of chemotherapy, in part via effects on MAPK1). On the other hand, a study in rats found that tobacco smoke activates MAPK1 and related pathways in the animals’ lungs.
However it happens, over-activity of the MAPK1 gene and its ERK1/2 protein can spur the growth of cancers in organs throughout the body. But that means the pathway gives us a place to hit cancer where it hurts. In fact, statin drugs taken by many people for their cholesterol-lowering effects incidentally seem to protect against cancer and cancer-related deaths, apparently by dampening the MAPK signal.
Scientists have been working on drugs to target components of the MAPK pathway much more intentionally. They liken cancer’s dependency on MAPK and other molecular pathways to addictions. If cancer were to suddenly lose its molecular pathway (or “drug”) of choice, then perhaps those malignant cells would flounder and die.
Much of the focus for drugs to keep ERK1/2 from reaching the cell nucleus out of turn has centered on a kinase called MEK. (MEK is a protein whose job is to turn ERK1/2 on.) MEK inhibitors have shown promise for treating many cancers, including leukemia as well as those of the thyroid, ovary, and skin. In 2014 the FDA approved a MEK inhibitor for use in treating select cases of melanoma. Drugs targeting the BRAF protein have gained approval for some uses too.
But cancer cells are tricky opponents. With targeted treatment delivered over time, malignant cells sometimes find ways to survive or even thrive in a matter of months. Studies suggest that resistance to inhibitors targeting upstream components of the pathway might be overcome with drugs that hit ERK1/2 itself. At least one clinical trial is underway for the use of an ERK1/2 inhibitor in patients with either acute myelogenous leukemia (AML) or Myelodysplastic Syndrome, a condition that sometimes progresses to AML.
MAPK1 and its molecular cronies play an important role in another odd sort of scenario. Sometimes, as cancer cells evolve and change in response to treatment, they find themselves addicted to the very drugs meant to kill them. Researchers suggest there may be a way to exploit this “unintentional weakness of cancer.”
Whether that pans out or not, it’s clear that the story of MAPK1, cancer, and its treatment is a work in progress. As the science advances, let’s hope for a lasting and reliable way to get MAPK1 and related cancers to stop and hear us for a change.