Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

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Autophagy has a complex dual role in tumor survival or cell death owning to that is an evolutionarily conserved catabolic mechanism and provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Hyperthermia is a rapidly growing field in cancer therapy and many advances have been made in understanding and applying the mechanisms of hyperthermia. The shallow oral and maxillofacial position and its abundant blood supply are favorable for the use of hyperthermia. However, the relationship between hyperthermia and autophagy has not been examined of oral squamous cell carcinoma (OSCC) in the tumor hypoxia microenvironment. Here, the expression level of autophagy relative genes is examined to explore autophagy effect on the responses of hyperthermia, hypoxia, and innutrition tumor microenvironment. It is founded that hyperthermia and hypoxia cause autophagy in starvation conditions; further, in hypoxia and innutrition tumor microenvironment, hyperthermia combines YC-1 and 3-MA could inhibit HIF-1α/BNIP3/Beclin1 signal pathway and decrease the secretion of HMGB1; moreover, the cell apoptosis rate increases with an inhibited of cell migration capacity. Thus, the present study demonstrated that combined use of YC-1 and 3-MA might increase the death of tumor cells in physiological and hyperthermic conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro, which offers new insight into the therapy of OSCC and its application in treating others study carcinomas.

Objective: Oral squamous cell carcinoma (OSCC) represents one of the main types of head and neck malignant tumors with high incidence and mortality as well extremely poor prognosis. Hyperthermia (HT) shows great promises for tumor therapy. However it can promote autophagy in tumor microenvironment, which is found to serve as a surviving mechanism for cancer cells. Inhibiting autophagy has been considered as an adjuvant anti-cancer strategy. The present study investigated the role of HT-induced autophagy, while attempting to combine chemotherapy and autophagy blocking with HT in OSCC cells under hypoxia and starvation microenvironment.Materials and methods: HIF-1α and Beclin-1 expression in tissues was determined by immunohistochemistry in 80 OSCC sample pairs. The IC50 of CoCl2, YC-1 (an inhibitor of HIF-1α) and 3-MA (an inhibitor of autophagy) was detected by CCK-8. CoCl2 and complete culture medium without serum were used to achieve the hypoxic and nutrient deficient microenvironment, respectively. HT was performed by heating in a 42 ℃ water bath. The role of HT and YC-1,3-MA on autophagy in vitro were assessed by qRT-PCR and Western blot, and the secretion of high mobility group box1 (HMGB1) was determined by ELISA. The migration and apoptosis rates of cells were assessed by wound healing assay and flow cytometry.Results: We observed that HIF-1α and Beclin1 were highly expressed in OSCC tissues, which were correlated with more advanced malignancy features. CoCl2 could establish hypoxia microenvironment, induce HIF-1α expression with dose-dependence as well as promote cell migration in Cal-27 and SCC-15 cells. Notably, hyperthermia and hypoxia could activate the HIF-1α/BNIP3/Beclin1 signaling pathway and promote HMGB1 secretion, which triggered cytoprotective autophagy to counteract the hypoxia and starvation cellular stresses, as indicated by downregulation of p62 and light chain 3-II (LC3 II). Furthermore, we found that hyperthermia combined YC-1 and/or 3-MA suppressed autophagy and cell migration whereas facilitated cell apoptosis.Conclusion: The present study demonstrated that combined use of YC-1 and 3-MA might increase death of tumor cells in physiological and hyperthermia conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro.