Importance of Biomarker Testing for RET in Non Small Cell Lung Cancer - Episode 2

MOA and Rationale for RET Inhibitor Development

Transcript: Robert Doebele, MD, PhD: The role of the RET receptor tyrosine kinase in normal cell development is that it allows for neuronal cells and enteric neuronal cells to develop. That includes division proliferation and migration of cells. And so it’s very akin to other proto-oncogenes in that it drives programs that cancer cells like to hijack in order to drive cancer cell growth, proliferation, and metastasis.

RET fusions bring together 2 unrelated genes. The portion of the RET receptor tyrosine kinase that is retained is the kinase domain. That’s the active signaling part. Then it’s typically fused to an unrelated gene that allows both its expression and constitutive activation without the presence of growth factor ligands that typically stimulate the RET receptor tyrosine kinase.

In cancer, there are many variations of RET gene fusions. In lung cancer, the predominant RET gene fusion is KIF5B, which occurs in approximately 60% of cases. There are many other gene fusion partners that include CCDC6, COA4, and many others. Interestingly, in non—lung cancer cases, KIF5B has never been identified, so there is some tissue specificity and some cancer specificity to the type of gene fusions that are identified in different types of cancer.

The prevalence of RET gene fusions and lung cancer is approximately 1% to 2%, and it also occurs rarely in other cancers. The only cancer where it occurs at a much more frequent rate are papillary thyroid cancers.

RET inhibitors are meant to be ATP mimetics, just like other small tyrosine kinase inhibitors, similar to EGFR inhibitors, ALK inhibitors, ROS1 inhibitors. By displacing ATP, they block the signaling activity of these potent oncogenes and thus cause either apoptosis or cell death of the cancer cell, or proliferation inhibition, so they stop the growth of these cells. The idea is very similar to other small-molecule tyrosine kinase inhibitors that we developed for other oncogenes in cancer.

Transcript Edited for Clarity