Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies

Román-Gil, María San; Pozas, Javier; Rosero-Rodríguez, Diana; Chamorro-Pérez, Jesús; Ruiz-Granados, Álvaro; Caracuel, Ignacio Ruz; Grande, Enrique; Molina‐Cerrillo, Javier; Alonso‐Gordoa, Teresa

doi:10.1016/j.ctrv.2022.102372

Cited by 20 publications

(18 citation statements)

References 163 publications

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Section: Ret -Targeted Therapiesmentioning

confidence: 99%

“…Some specific mutations are expected to cause acquired resistance to MKI treatments ( 12 ). Preclinical studies have shown that acquired gatekeeper mutation V804L is associated with MKI resistance ( 12 ). The emergence of a V804M mutation was reported in a patient with RET-mutant, sporadic MTC treated previously with multiple MKIs ( 74 ).…”

Section: Ret -Targeted Therapiesmentioning

confidence: 99%

“…This leads to aberrant RET overexpression, ligand-independent dimerization, and kinase activation ( Figure 1 B ). Notably, the RET fusion partner may influence the oncogenic potential of the chimeric RET protein affecting the intracellular location of the RET kinase (consequently the activated signaling pathways), and its expression levels ( 12 ). In addition, the altered function of the fusion partner may also have a role in the neoplastic transformation ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

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Precision oncology for RET-related tumors

et al. 2022

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Aberrant activation of the RET proto-oncogene is implicated in a plethora of cancers. RET gain-of-function point mutations are driver events in multiple endocrine neoplasia 2 (MEN2) syndrome and in sporadic medullary thyroid cancer, while RET rearrangements are driver events in several non-medullary thyroid cancers. Drugs able to inhibit RET have been used to treat RET-mutated cancers. Multikinase inhibitors were initially used, though they showed modest efficacy and significant toxicity. However, new RET selective inhibitors, such as selpercatinib and pralsetinib, have recently been tested and have shown good efficacy and tolerability, even if no direct comparison is yet available between multikinase and selective inhibitors. The advent of high-throughput technology has identified cancers with rare RET alterations beyond point mutations and fusions, including RET deletions, raising questions about whether these alterations have a functional effect and can be targeted by RET inhibitors. In this mini review, we focus on tumors with RET deletions, including deletions/insertions (indels), and their response to RET inhibitors.

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Section: Ret -Targeted Therapiesmentioning

confidence: 99%

Section: Ret -Targeted Therapiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Precision oncology for RET-related tumors

et al. 2022

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“…The different conformational structure of TKIs and the different way that TKIs and selective RET inhibitors bond to RET alter the response to drugs (46). Various mechanisms have been proposed for the drug resistance of RET-driven tumors, the main one being target modification (RET-dependent mechanisms of resistance) or bypass signaling (47,48).…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Medullary thyroid cancer: from molecular biology and therapeutic pitfalls to future targeted treatment perspectives

Saltiki

Simeakis

Karapanou

et al. 2022

European Journal of Endocrinology

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During the last decades knowledge on the molecular biology in medullary thyroid carcinoma (MTC) and specifically on the role of RET (rearranged during transfection) activating mutations in tumorigenesis has led to the evolution of novel targeted therapies, mainly tyrosine kinase inhibitors (TKIs). Vandetanib and cabozantinib have been approved for the management of metastatic progressive MTC. Two novel highly selective RET inhibitors, selpercatinib and pralsetinib, have recently been approved for the treatment of RET mutant MTCs and RET-fusion differentiated thyroid cancer (DTC). The administration of targeted therapies in MTC patients has changed the therapeutic strategies; however, in the majority of cases, there are no real data showing an improvement of prognosis by TKIs in MTC. Drug resistance remains the main reason for treatment failure. Thus, the understanding of the molecular landscape of tumorigenesis and the mechanisms underlying resistance to targeted therapies is of paramount importance for the further development of more efficient therapies for MTC. The present review focuses on the molecular pathways implicated in MTC tumorigenesis, the approved targeted therapies, the tumoral escape mechanisms as well as the future perspectives for targeted therapy.

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“…RET mutations can be divided into two groups: the ones present in the extracellular, cysteine-rich domain (CRD), and the ones present in the tyrosine kinase domain. The mutations occurring in the CRD fragment are mostly located in exons 8, 10 (codons 610, 611, 618, or 620), and 11 (codons 630 or 634) [ 40 , 41 , 42 ], and result in dimerization of mutant RET monomers and consecutive ligand-independent activation of the receptor [ 43 , 44 ]. Mutations in the cysteine-rich domain are more common for MEN2A and FMTC, with C634R in exon 11 representing 85% of detected mutations, whereas the tyrosine kinase domain (TKD) mutations are present more frequently in MEN2B.…”

Section: Mutationsmentioning

confidence: 99%

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

Kucharczyk

Krawczyk

Kowalski³

et al. 2022

Cancers

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Mutations and fusions of RET (rearranged during transfection) gene are detected in a few common types of tumors including thyroid or non-small cells lung cancers. Multiple kinase inhibitors (MKIs) do not show spectacular effectiveness in patients with RET-altered tumors. Hence, recently, two novel RET-specific inhibitors were registered in the US and in Europe. Selpercatinib and pralsetinib showed high efficacy in clinical trials, with fewer adverse effects, in comparison to previously used MKIs. However, the effectiveness of these new drugs may be reduced by the emergence of resistance mutations in RET gene and activation of different activating signaling pathways. This review presents the function of the normal RET receptor, types of molecular disturbances of the RET gene in patients with various cancers, methods of detecting these abnormalities, and the effectiveness of modern anticancer therapies (ranging from immunotherapies, through MKIs, to RET-specific inhibitors).

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Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies

Cited by 20 publications

References 163 publications

Precision oncology for RET-related tumors

Precision oncology for RET-related tumors

MANAGEMENT OF ENDOCRINE DISEASE: Medullary thyroid cancer: from molecular biology and therapeutic pitfalls to future targeted treatment perspectives

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

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