The Future of RET Inhibitors in Non-Small Cell Lung and Thyroid Cancer - Episode 2

RET Fusion, Point Mutation, and Signaling

Transcript: Marcia Brose, MD, PhD: A RET fusion is the result of the RET gene being spliced together with another gene. It is often found in papillary thyroid cancer in that form. That’s the contrast with medullary thyroid cancer, where you’ll actually have point mutations. So RET, when it’s altered in papillary thyroid cancer, is usually a fusion with another gene, and that happens in up to approximately 20% of patients.

RET point mutations, which are just a single mutation in a gene sequence, are usually associated with medullary thyroid cancer. And in medullary thyroid cancer there can be those mutations in 2 different formats, 1 of which is a sporadic mutation and the other 1 is a hereditary mutation. The difference is that a hereditary mutation is when the RET gene is altered, and it’s in all the cells of a patient and also can be, as it says, hereditary. It could be inherited from generation to generation. But the other point mutations can sometimes occur in the patients themselves. Up to 25%, 35% of patients can have the hereditary point mutation, and another 20% to 25% of patients can have the sporadic mutation. Up to 60% to 65% of patients will have 1 of the 2.

RET pathway and RET pathway activation are actually used in embryology, so in embryogenesis. It’s actually before birth. Most of the RET activity is already gone and not actually prevalent in a RET person once they’re born. That’s actually a good thing because that means we can target it without having a lot of adverse effects in an adult person.

How RET fusions can drive cancer development is that the RET gene has 2 parts. It has a functional part, which is the activating part that downstream turns on different parts of the cell to make it divide. And then what it’s spliced to, or what the point mutation does, is that it turns that part of the gene on nonstop. When that happens, it results in the cell dividing uncontrolled, instead of in the usual controlled way that would normally happen when the gene is being expressed more normally.

Transcript Edited for Clarity