The RET gene is important for controlling how cells grow and develop. When the RET gene is altered, it can cause cells to grow uncontrollably, leading to different types of cancer.
The RET proto-oncogene is a gene that provides instructions for cell growth and development, and changes in this gene can lead to cancer. The RET proto-oncogene plays a crucial role in the development and maintenance of various cell types. Alterations in this gene can lead to hereditary cancer syndromes such as multiple endocrine neoplasia. These alterations are particularly significant in specific cancers, such as medullary thyroid cancer and non-small cell lung cancers (NSCLC). Understanding the impact of RET alterations is essential for developing targeted therapies (add link here) and improving treatment options for patients.
Understanding the RET Gene and its Role in Cancer
The RET gene provides instructions for producing a protein that is involved in signaling within cells. The protein produced by the RET gene functions as a RET receptor, which plays a crucial role in the development and maintenance of various cell types, including nerve cells, kidney cells, and thyroid cells. This signaling is essential for normal cell growth and differentiation. However, alterations in the RET gene can lead to various types of cancer by causing abnormal cell proliferation.
RET Fusions in Non-Small Cell Lung Cancer
RET gene rearrangements or RET fusions, which occur when the DNA of the RET gene fuses with another gene, can lead to uncontrolled cell growth and the development of tumors. This alteration basically results in the RET molecule “on-off” switch getting stuck in the “on” position and causing tumor growth.
RET fusions are mostly present in RET positive NSCLC and papillary thyroid carcinoma, while RET somatic mutations are more commonly found in RET positive thyroid cancers. There are different types of RET rearrangements depending on the fusion gene partner. The most common RET fusion gene partner is KIF5B, and the second most common is CCDC6. At least 30 RET fusion partner genes have been identified to-date, and investigators are currently studying the characteristics of each one in cancer development and treatment. Identifying these rearrangements is important for understanding their implications in different cancer types and for their treatment using RET inhibitors.
The RET gene can also present somatic mutations, where one DNA base is changed. RET point mutations are most commonly found in medullary thyroid carcinoma.
Investigating Types of RET Fusions in Non-Small Cell Lung Cancer
Dr. John Heymach (MD Anderson Cancer Center), Dr. Marc Ladanyi (Memorial Sloan Kettering Cancer Center), and Dr. Ralf Kittler (UT Southwestern Medical Center) are working together to establish a comprehensive landscape of RET fusions and mutations associated with RET inhibitor resistance. This will allow the functional classification subgroups of RET mutations based on their differential response to RET therapies. These links provide more information about the RET gene and RET inhibitors and RET cancer updates.
RET Alteration Diagnosis
How RET Alterations are Diagnosed
RET alterations are identified through tumor biopsy and using comprehensive molecular testing called next-generation sequencing.
RET fusions also can be found using liquid biopsies, which is a test done on a sample of blood to look for circulating cancer cells or small pieces of DNA, RNA, or other molecules released by tumor cells into a person’s bloodstream.
If a RET alteration is detected using a liquid biopsy test, the results are reliable. But if it’s not detected, comprehensive molecular testing on tumor tissue is still necessary to rule out the alteration.
Treatment Options
Treatment Options for RET Positive Lung Cancer
First-line treatment options for RET-positive stage IV lung cancer patients are targeted therapies including the FDA-approved selective RET inhibitors that specifically target or inhibit the RET molecule: selpercatinib (Retevmo) and pralsetinib (Gavreto). The FDA approval of these agents was based on the positive results reported in the LIBRETTO-001 (NCT03157128) and ARROW (NCT03037385) clinical trials respectively. These RET inhibitors specifically target the RET fusion protein and showed great benefit in RET fusion positive NSCLC patients along with reduced side effects. Specific RET inhibitors are the preferred therapeutic option when compared with other cancer therapies such as multikinase inhibitors, chemotherapy, or immunotherapies based on immune checkpoint inhibitors.
Glossary
RET gene:
A gene that helps regulate cell growth and development, especially in nerves and other tissues.
RET mutation:
A change in the RET gene that can cause cells to grow abnormally, sometimes leading to cancer.
RET inhibitor:
A type of drug that blocks the activity of the RET gene to slow or stop the growth of cancer cells.
RET fusion:
A genetic change where part of the RET gene joins with another gene, which can drive cancer growth.
RET altered cancers:
Cancers that develop due to changes or mutations in the RET gene, leading to abnormal cell growth.
RET receptor:
A protein on the surface of cells that the RET gene produces, which helps send signals that control cell growth and development.
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