Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

Abstract

Pharmaceutical therapies are essential for esophageal cancer (EC). For the advanced EC, the neoadjuvant therapy regimen, including chemotherapy plus radiotherapy and/or immunotherapy, is effective to achieve clinical benefit, even pathological complete response. For the unresectable, recurrent, and metastatic EC, the pharmaceutical therapy is the limited effective regimen to alleviate the disease and prolong the progression-free survival and overall survival. In this review, we focus on the pharmaceutical applications in EC treatment including cytotoxic agents, molecular targeted antibodies, and immune checkpoint inhibitors (ICIs). The chemotherapy regimen is based on cytotoxic agents such as platinum-based complexes, fluorinated pyrimidines and taxenes. Although the cytotoxic agents have been developed in past decades, the standard chemotherapy regimen is still the cisplatin and 5-FU or paclitaxel because the derived drugs have no significant advantages of overcoming the shortcomings of side effects and drug resistance. The targeted molecular therapy is an essential supplement for chemotherapy; however, there are only a few targeted therapies available in clinical practice. Trastuzumab and ramucirumab are the only two molecular therapy drugs which are approved by the US Food and Drug Administration to treat advanced and/or metastatic EC. Although the targeted therapy usually achieves effective benefits in the early stage therapy of EC, the patients will always develop drug resistance during treatment. ICIs have had a significant impact on routine clinical practice in cancer treatment. The anti-programmed cell death-1 monoclonal antibodies pembrolizumab and nivolumab, as the ICIs, are recommended for advanced EC by several clinical trials. However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. These defects of pharmaceutical therapy restrain the clinical application and diminish the effectiveness of treatment.

The Role of lncRNA PCAT6 in Cancers

“…PCAT6 is a potential diagnostic biomarker, as well as a possible new prognostic biomarker. In past decades, cytotoxic chemotherapy has been developed, but has no significant advantages for overcoming drug resistance (62). However, accumulating studies have demonstrated that lncRNAs play important roles in chemotherapy resistance (63,64).…”

Reticulocalbin3: A Ca2+ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance

“…Then the whole score of protein expression was calculated with the value of the positive percentage score × staining intensity score, ranging from 0 to 12. The final expression level of RCN3 was defined as "low" (0-6) or "high" (7)(8)(9)(10)(11)(12), and the final expression level of HIF-1α was defined as "low" (0-3) or "high" (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

“…The 5‐year survival rate of EC patients is reportedly only approximately 20% 3 . Poor prognoses of ESCC are attributed to early metastasis and platinum‐based chemotherapy resistance 4,5 . Therefore, looking for more sensitive and specific molecular targets of ESCC is of great importance for the cure of this malignant disease.…”

Long noncoding RNA SNHG6 silencing sensitized esophageal cancer cells to 5-FU via EZH2/STAT pathway

“…Although new chemotherapeutic drugs and chemotherapy protocols have been rapidly updated in recent years, 5-fluorouracil (5-FU)-based chemotherapy protocols still have critical effect on treating EC 19 , 20 . Nonetheless, chemotherapy resistance is still the biggest factor limiting the clinical application of 5-FU in EC, and its molecular mechanism is complex and changeable 21 . Accumulating evidence has shown that lncRNA is becoming a star molecule affecting tumor chemotherapy 22 , 23 .…”