Protein sentenced to ‘forced labor’ causes cancer drug resistance

There is nothing more devastating for a cancer patient and their family than an effective treatment that suddenly stops working and the tumor returns more aggressively. Unfortunately, resistance to monotherapy (based on a single drug) is quite common. Studying and knowing the molecular mechanisms that cause it is the key to treating cancer patients.

Through collaborative work my laboratory at the IMDEA Food Institute and the Dr. James Fagin Institute in New York (MSKCC), we have discovered a new cause of resistance in thyroid cancer with mutations in the BRAF gene: protein delocalization within the cell. It’s not just that this protein is not where it should be, but that it is “forced” to be “in the wrong place.”

When drugs don’t work

Drug resistance is defined as the ability of cancer cells to overcome the effects of a drug and survive. In this disease, two main types of resistance are distinguished: congenital and acquired.

First, a group of cells in a tumor has a pre-existing genetic change or cellular condition (which is unknown) and is not responsive to drugs. For its part, acquired resistance occurs during treatment, when cancer cells look for alternative pathways to compensate for the function of the pathway blocked by the drug in order to survive.

“plumbing” problems

In a very simplified way, let’s think of molecular pathways as a system of conduits that connect to each other in a very complex pattern, of which we only know a fraction; the rest is hidden and we don’t know their proportions.

There is a leak, water everywhere (swelling). We are looking for the reason and see that in one of the pipes the stopcock does not close, it is broken (mutation). The solution is simple: we block the pipeline (treatment). But to our surprise, after a while, water resistance (resistance) continues to come out.

This can be caused by various reasons:

1. We search again and it turns out that another connection is broken (a new mutation).

2. The water is directed through a pipe that is not normally used (parallel routes).

3. The tube contains a substance that causes degradation of the blocking adhesive (metabolic adaptation and drug degradation).

Unfortunately, there is no single answer; The same does not occur in all types of tumors and not in all patients with the same type of tumor.

One reason is heterogeneity. A tumor is made up of its own cells—tumor cells themselves—which are also not exactly the same. Added to this is the so-called tumor microenvironment, which consists of supporting cells, cells of the immune system, cells of the vascular system, etc.

To top it off, there are also differences between different patients affected by the same type of tumor. To make another comparison, let’s think of a strawberry shortcake contest that has an infinite number of different flavors and recipes. Even if they are made from the same recipe, they taste different, right?

And finally, the tumor evolves over time. In other words, although it initially arises as a result of a change in one cell and reproduces uncontrollably, the daughter cells acquire new characteristics that distinguish them from their parents, like life itself.

YAP1 does not return to its site

Finding all of these options and alternatives is the key to overcoming drug resistance and treating cancer patients. This is the case of YAP1, the main protein for cell function, whose “resting place” is the cell cytoplasm and whose “workplace” is the nucleus.

Under normal conditions, YAP1 moves to the nucleus to induce the expression of genes associated with the normal functioning of the cell, and, having completed its task, returns to the cytoplasm. If this relocation does not occur, YAP1 remains constitutively activated in the nucleus, overloading the system and expressing genes associated with tumor formation and treatment resistance.

In BRAF-mutated thyroid cancer, we confirmed that treatment with a specific inhibitor of this protein was not effective for those tumors in which YAP1 was fixed in the nucleus (intrinsic resistance). And tumors with YAP1 in the cytoplasm (after the initial action of the drug) became resistant, as the protein returned to the nucleus. If we added a YAP1 blocking treatment to the inhibitor, it would be effective again.

It is clear that this is much more difficult. But there is a promising strategy to better attenuate drug resistance and increase patient survival. It will consist of administering an initial combination therapy that prevents or delays the development of tumors and/or dynamically modifying such treatment during tumor response before resistance fully emerges.

Maria Elena Rodriguez Garcia-Rendueles, Principal Investigator: Thyroid Cancer, IMDEA FOOD

This article was originally published on The Conversation. Read the original.