Why RET Alteration is an Attractive Target for Therapy

Jacob Sands, MD: RET is a transmembrane receptor with a tyrosine kinase domain that’s intracellular. This is accessible to targeted therapies and can potentially become an oncogenic driver for cells. This happens with RET fusions or mutations; in lung cancer, we typically see this as a fusion. This is important to understand because when we have effective targeted therapies that can hit these surface receptors, which impact the oncogenic driver, we can see really significant responses to therapy. And this is something we’ve noted with previously discovered targeted therapies within EGFR, ALK, ROS1. We’re seeing this paradigm currently happening, and now RET is a receptor that is accessible for this as well.

So the difference between fusion and a point mutation is something that is relevant to the discussion within lung cancer in general, and we see point mutations—which is just the change in 1 of the nucleotides—and we see that with, for example, T790M, a mutation within the EGFR setting. Fusions are more of a hybrid from 2 different areas in the genetic code, and we see that ALK, ROS1, and now with RET as well. Either of these alterations can become oncogenic drivers of the cells, so the downstream impact of that change in the code really becomes important.

In some cases, whether it’s a fusion or a mutation, it doesn’t actually impact decision making. But we do see differences in the tendencies within these different genes.

In non—small cell lung cancer, as far as the RET gene, it’s much more common to see fusions as opposed to mutations. Mutations in RET are much more common within thyroid cancer. But in lung cancer we see RET fusions, KIF5B being the most common fusion in RET. There are others, of course, although that is the more common one.

And we see these fusions occurring in 1% to 2% of non—small cell lung cancer. We see this occurring in 1% to 2% of lung adenocarcinomas.

Benjamin Besse, MD, PhD: In lung cancer there are many partners with RET that can drive the fusions. The pathologist finds most frequently T5B and CCD C6. Is this really important? It matters for the previous multikinase inhibitors, but it seems that the most frequent T5B RET fusion was less sensitive to these drugs, but for the new selective inhibitors, it doesn’t matter. It has its importance in terms of screening because, when you run NGS [next-generation sequencing] panels, you have to know what the partner and the point fusion is to find this fusion. But for the clinician, it doesn’t matter very much.

RET can be activated in cancer cells through a fusion or a point mutation. These abnormalities activate RET in a constitutive way. And this activation drives oncogenesis in some cancer types, such as lung and thyroid cancers.

We know for example that in lung cancer such driver mutations can really impact the outcome of lung cancer when treated with a selective inhibitor. We have many examples with ALK inhibition and ROS1 inhibition. While RET works exactly the same way, RET inhibition has a strong way to treat the disease.

Transcript Edited for Clarity