RET signaling pathway and RET inhibitors in human cancer
Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinom...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.932353/full |
| _version_ | 1818042982118457344 |
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| author | Angelina T. Regua Mariana Najjar Hui-Wen Lo Hui-Wen Lo |
| author_facet | Angelina T. Regua Mariana Najjar Hui-Wen Lo Hui-Wen Lo |
| author_sort | Angelina T. Regua |
| collection | DOAJ |
| description | Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy. |
| first_indexed | 2024-12-10T08:54:58Z |
| format | Article |
| id | doaj.art-6f6137dc92574ac1af894e319c6f7090 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T08:54:58Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-6f6137dc92574ac1af894e319c6f70902022-12-22T01:55:27ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.932353932353RET signaling pathway and RET inhibitors in human cancerAngelina T. Regua0Mariana Najjar1Hui-Wen Lo2Hui-Wen Lo3Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United StatesDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United StatesDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United StatesWake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, United StatesRearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy.https://www.frontiersin.org/articles/10.3389/fonc.2022.932353/fullRETcancertherapeuticslung cancerthyroid cancer |
| spellingShingle | Angelina T. Regua Mariana Najjar Hui-Wen Lo Hui-Wen Lo RET signaling pathway and RET inhibitors in human cancer Frontiers in Oncology RET cancer therapeutics lung cancer thyroid cancer |
| title | RET signaling pathway and RET inhibitors in human cancer |
| title_full | RET signaling pathway and RET inhibitors in human cancer |
| title_fullStr | RET signaling pathway and RET inhibitors in human cancer |
| title_full_unstemmed | RET signaling pathway and RET inhibitors in human cancer |
| title_short | RET signaling pathway and RET inhibitors in human cancer |
| title_sort | ret signaling pathway and ret inhibitors in human cancer |
| topic | RET cancer therapeutics lung cancer thyroid cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.932353/full |
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