Kevin Dalby
Kevin Dalby

Signal transduction — the transmission of molecular signals from the exterior of a cell to its interior — is an important focus of cancer drug discovery research. Proteins transmit messages needed for cells to function normally. In this article, UT-Austin professor, Kevin Dalby, discusses what happens when cells start to ignore normal signals and why this may happen.

There are proteins, called receptors, that sit on the surface of a cell. As indicated by their name, receptors receive signals or messages from signaling molecules outside the cell and convey messages to the proteins within the cell. These amplified messages instruct the cell, telling it how to behave. The instructions may include directions to grow, die, or secrete a protein, for example. The receptor binds the signal molecule and then initiates a response in the target cell.

These conversations are going on all the time within our bodies. Cells receive and respond to multiple signals at once. Multiple signal transduction pathways create a network through which the cell integrates information from its environment.

Cancer cells can multiply in a culture dish outside of the body. Unlike normal cells, they do not require that growth-stimulating protein signals be present. Cancer cells may make their own growth factors. In effect, they have growth factor pathways that are stuck in the “on” position. They will even trick neighboring cells into producing growth factors to sustain them.

A protein called KRAS — a short name for the gene Kirsten rat sarcoma viral oncogene homolog — has been found by researchers to be mutated in about 90% of pancreatic cancer cases. KRAS is a member of a group of genes associated with the epidermal growth factor receptor (EGFR) pathway.

Another trademark of cancer cells is their “replicative immortality.” They divide many more times than a normal cell. Normal cells go through only about 40-60 rounds of division before they lose the capacity to divide. Cancer cells divide many more times than this. They express an enzyme called telomerase. Among other things, telomerase reverses the wearing down of chromosomes during each cell division.

When mutated, KRAS bypass receptors and signal cells directly, telling them to grow and survive. Instruction from these hyperactive RAS/MAPK pathways can cause cells to form a tumor. The cells never receive a “stop growing” or “it’s time to die” signal, so they continue to grow.

One of the difficulties with traditional cancer treatments, such as chemotherapy and radiation therapy, is that they target all actively growing cells. These treatments cannot discriminate between healthy cells and cancerous ones. Severe and even life-threatening side effects can occur as healthy and necessary cells are affected by these therapies.

A better understanding of the signaling pathways that are hyperactive in cancer cells may lead to improved treatments. The hope is that as we come to understand signal transduction better, we will be able to develop treatments that affect only cancer cells without interfering with healthy ones.

More in-depth knowledge of signal transduction has already led to improved drugs used to treat leukemia and breast cancer. Labs, many funded by the Pancreatic Cancer Action Network, are working to build on these successes and learn to apply them to pancreatic cancer treatment.

About Kevin Dalby

Dr. Kevin Dalby is a UT-Austin medicinal chemistry professor. He is researching the mechanisms of cancer cell signaling to develop targeted therapeutics. Dr. Dalby’s efforts were recognized by the Cancer Prevention and Research Institute of Texas (CPRIT) and the National Institutes of Health, granting him nearly $5 million to support his research.