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BIOMARKER:

RET V804M

i
Other names: RET, Ret Proto-Oncogene, Proto-Oncogene Tyrosine-Protein Kinase Receptor Ret, Cadherin-Related Family Member 16, Rearranged During Transfection, RET Receptor Tyrosine Kinase, Cadherin Family Member 12, Proto-Oncogene C-Ret, CDHF12, CDHR16, PTC, Ret Proto-Oncogene (Multiple Endocrine Neoplasia And Medullary Thyroid Carcinoma 1, Hirschsprung Disease), Multiple Endocrine Neoplasia And Medullary Thyroid Carcinoma 1, Hirschsprung Disease 1, RET-ELE1, HSCR1, MEN2A, MEN2B, RET51, MTC1
Entrez ID:
2ms
Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict? (PubMed, Cancers (Basel))
Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.
Journal
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RET (Ret Proto-Oncogene)
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RET V804M • RET V804*
11ms
A Case of Simultaneous Medullary Thyroid Cancer (MTC) And Papillary Thyroid Cancer (PTC) In a Patient With Germline RET Mutation (ENDO 2023)
Coexistence of MTC and PTC in germline RET mutation is an uncommon association and more information is required to understand common features, risk factors, phenotype and cancer aggressiveness in these patients. At this point it cannot be concluded that the association is a mere coincidence.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.
Clinical
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RET (Ret Proto-Oncogene)
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RET mutation • RET V804M • RET V804*
11ms
Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male (ENDO 2023)
The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease.
Clinical
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RET (Ret Proto-Oncogene)
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RET M918T • RET V804M • RET C634* • RET V804*
2years
The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor (AACR 2022)
Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.
Preclinical
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RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • KDR (Kinase insert domain receptor) • CCDC6 (Coiled-Coil Domain Containing 6)
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RET fusion • RET mutation • RET M918T • RET C634W • RET V804L • RET V804M • RET C634* • RET V804*
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Retevmo (selpercatinib) • Gavreto (pralsetinib) • APS03118
over2years
Controversy on the management of patients carrying RET p.V804M mutation. (PubMed, Endocrine)
Despite the controversy and the heterogeneous presentation of patients with RET p.V804M mutation, our study and review of the literature suggest that this seemingly "low" risk mutation is associated with late-onset but potentially aggressive MTC. This indicates the need for follow-up and timely intervention based on calcitonin level elevation.
Clinical • Journal
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation • RET mutation • RET V804M • RET V804*
over2years
[VIRTUAL] LIBRETTO-531: A Phase III study of selpercatinib vs investigator choice of cabozantinib or vandetanib in patients with multikinase inhibitor-naïve advanced or metastatic RET-mutant medullary thyroid cancer (MTC) (AHNS 2021)
This study is active and recruiting, with planned enrollment of 400 participants at ~150 sites in 21 countries. In response to the global COVID-19 pandemic, mitigations for patient safety are included in the protocol.
Clinical • P3 data
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RET (Ret Proto-Oncogene)
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RET mutation • RET M918T • RET V804M • RET V804*
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Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Caprelsa (vandetanib) • Cometriq (cabozantinib capsule)
almost3years
Discovery and Optimization of Selective RET Inhibitors via Scaffold Hopping. (PubMed, Bioorg Med Chem Lett)
Currently, several approved multikinase inhibitors such as vandetanib and cabozantinib demonstrate clinical activity in patients with RET-rearranged or RET-mutant cancers...Herein, we designed and synthesized a series of RET inhibitors based on the structure of selective RET inhibitor BLU-667 and investigated their biological activities...In mouse xenograft models, compound 9 repressed tumor growth driven by KIF5B-RET-Ba/F3 cells in a dose-dependent manner. Based on its exceptional kinase selectivity, good potency and high exposure in tumor tissues, compound 9 represents a promising lead for the discovery of RET directed therapeutic agents and the study of RET-driven tumor biology.
Journal
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RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B)
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RET fusion • RET mutation • KIF5B-RET fusion • RET M918T • RET V804M • RET V804*
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Cabometyx (cabozantinib tablet) • Gavreto (pralsetinib) • Caprelsa (vandetanib)
3years
[VIRTUAL] Pre-clinical characterization of potent and selective next-generation RET inhibitors (AACR 2021)
Previous studies in pts treated with selpercatinib or pralsetinib have reported the shared emergence of recurrent RET G810 mutations at the solvent front of the ATP pocket, which lead to a steric clash and loss of binding potency for both drugs. These data suggest that LOX-18228, as well as closely related compounds, represent promising next-generation RET inhibitor candidates that could be used to further extend durable disease control for pts with RET-altered cancers following the development of acquired resistance to current agents. An IND is planned for 2021.
Preclinical
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RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6)
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RET fusion • RET mutation • KIF5B-RET fusion • RET M918T • RET V804M • RET V804* • RET positive
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Retevmo (selpercatinib) • Gavreto (pralsetinib)
over3years
Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant. (PubMed, Eur J Med Chem)
In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
Journal
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RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6)
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RET mutation • KIF5B-RET fusion • RET V804L • RET V804M • RET positive
over3years
Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation. (PubMed, Eur J Med Chem)
Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
Journal
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RET (Ret Proto-Oncogene) • CCDC6 (Coiled-Coil Domain Containing 6)
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RET fusion • RET mutation • RET V804M
over3years
[VIRTUAL] LIBRETTO-531: Selpercatinib in patients with treatment (Tx)-naïve RET-mutant medullary thyroid cancer (MTC) (ESMO 2020)
This global, open-label, randomized, controlled, phase III trial will compare selpercatinib to physician choice of cabozantinib or vandetanib in pts with MKI-naïve progressive advanced or metastatic RETmut MTC...Funding: Eli Lilly and Company. Clinical trial identification: NCT04211337.
Clinical
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RET (Ret Proto-Oncogene)
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RET mutation • RET M918T • RET V804M • RET V804M + M918T
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Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Caprelsa (vandetanib)
almost4years
[VIRTUAL] The Anti-Tumor Activity of the Selective Ret Inhibitor Selpercatinib (LOXO-292) in Medullary Thyroid Cancer Is Independent of the Specific RET Mutation (ENDO-I 2020)
Among the primary analysis set of patients with RET-mutant MTC previously treated with cabozantinib and/or vandetanib (N=55), the investigator-assessed objective response rate (ORR) per RECIST 1.1 was 56% (95% CI 42.3-69.7, n=31/55)...As previously reported, selpercatinib was well tolerated with an acceptable safety profile (1). These results indicate broad anti-tumor activity for selpercatinib in patients with RET-mutant MTC irrespective of the specific RET mutation, and support implementation of RET mutation testing for patients with advanced MTC, including somatic testing, to identify patients who may benefit from selpercatinib.
Late-breaking abstract
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RET (Ret Proto-Oncogene)
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RET fusion • RET mutation • RET M918T • RET V804M • RET V804M + M918T • RET positive
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Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Caprelsa (vandetanib)