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RET kinase inhibitors for the treatment of RET-altered thyroid cancers: Current knowledge and future directions
1Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, 77030, USA.
Abstract:
RET gain-of-function mutations are the most common drivers in medullary thyroid carcinoma, while RET fusions are identified in 5-10% of papillary thyroid carcinomas. Thus, RET plays a major role in the tumorigenesis of thyroid neoplasia, making it a valuable therapeutic target. Over a decade ago, multikinase inhibitors (MKIs) were first shown to have variable degrees of anti-RET activity. Despite some clinical efficacy in RET-altered thyroid cancers, significant off-target activity of MKIs led to marked toxicities limiting their use. More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. However, these treatments are non-curative, and emerging evidence suggests that patients who progress on therapy acquire mutations conferring drug resistance. Thus, the quest for a more definitive treatment for advanced, RET-altered thyroid cancers continues. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.
Insights
RET proto-oncogene alterations drive thyroid cancers, leading to targeted therapies like selective RET inhibitors. While effective, these treatments face resistance, necessitating research into more definitive therapies for advanced RET-altered thyroid neoplasms.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- RET proto-oncogene alterations, including gain-of-function mutations and fusions, are key drivers in thyroid neoplasia, particularly medullary and papillary thyroid carcinomas.
- RET is a validated therapeutic target in thyroid cancer, with early multikinase inhibitors (MKIs) showing limited efficacy and significant toxicity due to off-target effects.
- The 30th anniversary of linking germline RET mutations to multiple endocrine neoplasia (MEN) type 2 syndromes highlights the long-standing importance of RET in thyroid disease.
Purpose of the Study:
- To review current treatment strategies for RET-altered thyroid cancers.
- To discuss the limitations of existing therapies, including resistance mechanisms.
- To explore future therapeutic avenues for advanced, RET-altered thyroid neoplasms.
Main Methods:
- Review of scientific literature on RET alterations in thyroid cancer.
- Analysis of clinical efficacy and toxicity data for various RET-targeting agents.
- Examination of emerging evidence on drug resistance mechanisms.
Main Results:
- Selective RET inhibitors (selpercatinib, pralsetinib) demonstrate notable efficacy with improved tolerability compared to MKIs in RET-altered thyroid cancers.
- Current RET-targeted therapies are non-curative, and acquired drug resistance is a significant challenge.
- The development of novel therapeutic strategies is crucial for overcoming treatment resistance.
Conclusions:
- Targeted inhibition of RET offers a significant advancement in treating RET-altered thyroid cancers.
- Addressing treatment resistance and exploring non-curative therapeutic options remain critical research priorities.
- Continued investigation into novel therapeutic avenues is essential for improving outcomes in advanced thyroid cancer.
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