Cancer cells resist chemotherapy. Scientists just figured out why.

Chemotherapy — our main tool in combating cancer — has a problem. Scientists have noted that cancer cells seem to be resisting it, continuing to replicate and grow despite it. 

A recent study has shed light on just what is happening, suggesting that combating chemotherapy resistance and strengthening the effectiveness of the treatment may be possible.

Nearing the end of September, the Molecular Cell – a peer reviewed scientific journal — published a study on how chemotherapy treatments were being disrupted, and the solutions scientists have come up with.

There are all sorts of variables that could cause this resistance: either the cancer cell becomes insensitive and is therefore unaffected, or other tumor specific factors and gene expression. The recent study focuses on one important aspect of that resistance.

Addressing this problem is important in part because when chemotherapy doesn’t work on a patient, the cancer cell is essentially left untreated, and all you can do at this point is to cut it out. Removing cancerous tumors through surgery is incredibly risky and how easily it’s removed highly depends on the tumor’s location. Chemotherapy helps reduce the size of cancerous tumors, and can sometimes completely rid the patient of cancer.

This specific paper was led by Diego Dibitetto from Cornell University, explains a process in which the DNA replication that causes cancer cell growth was not stopped by the therapy, but merely reversed in direction and continuing nonetheless, due to the presence of a particular protein. 

Generally, we prefer having DNA replication go through smoothly, so we don’t have mutations, or genetic diseases; in cancer cells, however, it benefits us if DNA replication doesn’t go smoothly, preventing cancerous cells from being able to replicate and grow.

DNA ligase DNA replication, Wikimedia Commons (https://upload.wikimedia.org/wikipedia/commons/6/6e/DNA_Ligase_DNA_Replication.png)

DNA replication happens when the nucleus decides that the cell is ready and has collected all the materials needed. A bunch of different proteins, like helicase, primers, and primase, attach to the DNA strand to “unzip” it — creating a “replication fork” — and copy it. During replication, the DNA gets “unzipped” by an enzyme (enzymes are catalysts and speed up reactions) called helicase, and it turns into something that looks a little like a ladder cut down the middle. Then the DNA polymerase comes in and makes a mirror copy of the DNA strand. These later come together to form two new strands of DNA.

DNA replication could be compared to a road,  with the proteins being the cars and the road being the actual DNA it’s traveling down. The chemotherapy drug is like a roadblock of sorts, or something like a pothole, where the cars go full force, 200km/hr, and slams right into the roadblock, completely obliterated and smashed to bits.This happens in the “bad” cancer cells to mess up its DNA, rendering it incapable to replicate and effectively making it unable to function. We use this as either a before treatment, to reduce the cancer cells and tumor in someone’s body, or to completely get rid of cancer cells. Chemotherapy tends to target rapidly duplicating cells, since cancer tends to replicate a lot faster than regular body cells; this is why chemo patients tend to lose hair and stomach lining, as those are the body cells that duplicate faster.

Now scientists started seeing that some cancer cells were becoming resistant to the chemotherapy drug, where the cancer isn’t affected even after treatment. After observing the cancer cells that were resisting the treatment, scientists found the protein-kinase — a type of enzyme-catalyst that speeds up reactions — that was responsible for all this: the DNA PKcs.

Protein kinases are usually proteins, which are in charge of adding chemicals to other molecules to make them active or inactive; essentially used to turn things on and off. and it helps make other enzymes and structures that we need to help repair DNA breaks during replication. 

The scientists behind this experiment used something called “DNA fiber assay” to watch the DNA replicate. After watching and running many tests, they found out that the DNA-PKcs was stopping and reversing the replication fork before replication hit the drug, so instead of replication continuing and smashing into the drug/roadblock (which is what we want), replication stops right before the roadblock, leaving the cancer cell’s DNA intact and able to keep replicating and making more. 

The scientists didn’t just figure out what was happening. They also found out how to stop it.

They ran a few tests and eventually determined that putting in PKcs inhibitors would — as the name suggests — inhibit the PKcs, and the cancer cell’s DNA would smash to bits once more!

This is a significant discovery that can potentially improve the recovery of cancer patients. Scientists can build upon this discovery and use this information as a building block for future issues in this field or similar ones. 

Chemo-resistance meant that our only way of combating cancer was weak, but now that scientists know why this is happening they can also figure out how to reverse it, and prevent it from happening in the first place.

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