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

Abstract

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.

Molecular genotyping in medullary thyroid cancer

“…MKIs and specific RET inhibitors have different structures and bind to RET in distinct ways; these differences result in variable responses to the drugs. Our understanding of resistance mechanisms is increasing [29 ▪▪ ]. The most common causes are either at the level of RET itself or the development of bypass mechanisms thereby escaping the blockade of a particular drug to growth of the tumour.…”

“…An example is the solvent front mutation RETG810S/R/C, where glycine substitution with cysteine, serine or arginine occurs and resistance to selective RET inhibitors selpercatinib and pralsetinib develops [31,32]. Saltiki et al [29 ▪▪ ] provide a helpful and comprehensive review of both gatekeeper and nongatekeeper mutations leading to drug resistance in MTC [29 ▪▪ ]. The development of mechanisms to bypass drug induced blockade by the activation of downstream pathways is also an active area of research.…”

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

“…Treatment of advanced and progressive MTC may require medical therapies, though the optimal treatment, dose and timing are debated ( 1 ). The multikinase inhibitors (MKIs) vandetanib and cabozantinib are approved for the management of metastatic progressive or symptomatic MTC ( 6 ). Since the crucial role of Rearranged During Transfection (RET) mutations in an relevant percentage of MTC cases ( 4 ), and the off-target toxicities often given by MKIs, two selective RET inhibitors, selpercatinib and pralsetinib have been evaluated and approved for patients with advanced or metastatic RET-mutant MTC, either somatic or germinal, and are currently the first lines of treatment for metastatic or progressive tumours presenting RET mutations ( 7 – 9 ).…”

“…Nevertheless, a significant impact on survival is still lacking. Furthermore, treatment toxicities and resistance may often cause treatment failure or withdrawal ( 6 ). Indeed, according to guidelines, stable or slowly progressive MTC are not suitable for these therapies ( 10 ).…”

Медулярний Рак Щитоподібної Залози: Особливості Лікувально-Тактичних Підходів Та Післяопераційного Менеджменту Пацієнтів

“…Крім того, у 16-30% RET-негативних карцином виявлені мутації RAS. Інші генетичні зміни, хромосомні перебудови чи точкові мутації в мінорних генах, зокрема і тих, що відповідають за виникнення інших типів раку ЩЗ, зустрічаються дуже рідко [11,[14][15][16][17].…”