Targeting autophagy in thyroid cancers

Abstract

Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10 2021-2035. (https://doi.

HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

“…Studies have indicated that gain of TERT function modulates the activity of the mammalian target of rapamycin (mTOR) and induces autophagy, which is required for metabolic rewiring, to scavenge the nutrients that are necessary for fueling cancer cell growth in a challenging tumor microenvironment (26,27). Increasing studies have supported the central role of autophagy in the maintenance and development of various kinds of cancers, including thyroid carcinoma (28). Specifically, autophagy plays important roles in regulating the dedifferentiation process of PTCs, although the data are limited (29).…”

The role of autophagy in the thyroid tumors development, connection with the AKT/m-TOR signaling pathway activation

“…Однако существование аутофагии, часто сопровождающей процессы развития резистентности, в том числе и к таргетным препаратам, может снижать эффект такого лечения. Такая постановка проблемы подразумевает развитие комплексных подходов в лечении данной категории больных, в том числе использование таргетных препаратов совместно с веществами, модулирующих процесс «самопоедания» [42].…”

“…Показано, что инициация аутофагии на ранних стадиях развития опухоли, до формирования у этих клеток инвазивных свойств и способности к метастазированию, приводит к гибели раковых клеток [34]. В дальнейшем, напротив, особенно на фоне противоопухолевого лечения, активная аутофагия сопровождается развитием метастазов, формированием рецидивов заболевания и резистентности опухоли к лечению [42]. Большинство исследователей сходятся во мнении, что стимуляция аутофагии является универсальным защитным механизмом, предотвращающим развитие рака.…”

“…Кроме того, доказано значение данного явления в развитии радиойодрезистентных раков щитовидной железы [46]. В качестве перспективных препаратов, способных снижать активность процесса аутофагии, могут быть использованы ингибиторы ULK1, Vsp34, ATG4B, ингибиторы лизосом, однако эффективность их применения до сих пор исследуется [15,42]. Стоит отметить, что развитие аутофагии, формирование условий для успешного применения противоопухолевых препаратов при папиллярном раке щитовидной железы определенным образом связано с состоянием сигнальных каскадов и ключевого из них -AKT/mTOR пути.…”

Polymer Nanoformulation of Sorafenib and All-Trans Retinoic Acid for Synergistic Inhibition of Thyroid Cancer

“…SOR exhibits an excellent antitumor effect on various thyroid cancer cell lines, including dedifferentiated subtypes, leading to tumor cell apoptosis and cell cycle arrest (Broecker-Preuss et al, 2015). Nevertheless, drug resistance and serious adverse events, including hand-foot skin reactions, diarrhea, and hypertension, limit the clinical application of SOR (Wei et al, 2019). Studies have shown that patients with DTC have a higher incidence of adverse events to SOR compared to patients with renal and hepatocellular cancer, and about half of the patients need to reduce the dose to control drug toxicity in phase 2 and 3 trials (Jean et al, 2016).…”