Let’s talk about cancer! Specifically, HER2 + breast cancer. This type represents 15-20% of breast tumors, tumors with high aggressiveness and poor prognosis. Despite the existence of therapies, only a small percentage of patients respond, and the remaining majority end up showing resistance to drugs.
In this scenario, a group of researchers from the Research Center for Molecular and Cellular Biology of Cancer in Salamanca, in combination with the San Carlos Clinical Hospital in Madrid, have developed a new therapeutic alternative called EV20-MMAF: the combination of an antibody with a cytotoxic drug.
Let’s start from the beginning. Broadly speaking, we can differentiate three breast tumor types: those that overexpress hormone receptors (estrogens and prostanglandins, ER + / PR +) on their surface, those that overexpress the HER2 receptor (HER2 +) and the triple negative ones (ER- / PR- / HER2-) that do not overexpress any of these receptors.
In this case, we will focus on HER2 + breast tumors and to understand how they behave we must talk about the concept of cell signaling (or cell signaling cascades, or cell signaling pathways …). The cells of our body are prepared to respond to different types of signals. Let’s take the example of a hormone. A hormone is produced by a gland in our body, but it acts on some specific cells in the body. Only cells that have receptors for that hormone will respond to it.
Receptors are proteins that are located on the membrane of our cells, “looking outward.” Thus, the binding of the hormone with its receptor causes it to change its shape and can interact with and activate another protein inside the cell. This last protein can activate another, and this one, another. Until it is the turn of a protein with the ability to enter the nucleus of our cells and modulate the expression of genes. This type of protein is called a transcription factor and is capable of entering the nucleus and interacting with the genes for which it has specificity. In this way, it is able to induce or block its expression.
Gene activation or inhibition causes the cell to respond in one way or another. If, for example, a gene that codes for a protein that acts in cell proliferation is activated, the result of this initial hormone will be the proliferation of the cell. This is the simplest and most general cellular signaling concept to keep in mind.
There are a multitude of signaling pathways, each with its receptors (which respond to one molecule or another), with its specific proteins inside the cell and which end up modulating different genes (proliferation, death, growth …).
But let’s go back to breast cancer. HER2 + tumors overexpress this receptor on the surface of their cells. This protein appears normally in breast cells, however, in this tumor type, the gene that produces it is altered. The result is that the protein it codes for, the HER2 receptor, produces more than it should.
HER2 is a receptor in the epidermal growth factor receptor (EGFR) family. This HER2 protein is involved in activating signaling pathways for survival, proliferation … In addition, it has a peculiarity, it is a receptor that does not have a ligand, it activates by itself and is capable of activating the entire signaling pathway. What happens if it is overexpressed in cancer cells? Which will trigger more proliferation than is required: perfect for tumor progression right?
Ana, C., Juliana, R., Juan, O., & Daniel, M. (2015). HER-2: A molecular marker used in the diagnosis, prognosis, and treatment of breast cancer. Risaralda Medical Journal, 21 (1), 31–37.
How is this type of breast cancer treated? Trying to block HER2 receptor activity. For this, there are two alternatives: antibodies that bind to the external part (which protrudes from the cell) such as Trastuzumab or Pertuzumab; or molecules that attack the internal part, which interacts with the first protein in the pathway (Lapatinib). Both alternatives are generally always used in combination with chemotherapy, and the goal is the same, to block the signaling that this receptor initiates.
The problem with this tumor type? That it is capable of developing resistance to these drugs. Resistance is nothing more than the ability acquired by a tumor to stop a previously destructive drug from being destructive. In this case, the tumor cells alter the shape of the HER2 receptor (so that it is not recognized by the drugs), or even acti