Mechanisms of Resistance to Chemotherapy in Gastric Cancer

Abstract

Although surgical resection is the standard curative therapy for gastric cancer, these tumors are often diagnosed at an advanced stage, when surgery is not recommended. Alternative treatments such as radiotherapy and chemotherapy achieve only very modest results. There is therefore an urgent need to advance in this field of oncologic gastroenterology. The poor response of gastric cancer to chemotherapy is usually due to a combination of mechanisms of chemoresistance (MOC), which may include a reduction in drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), a reduced proportion of active agents in tumor cells due to a reduction in pro-drug activation or an enhancement in drug inactivation (MOC-2), changes in the expression/function of the molecular targets of anticancer drugs (MOC-3), an enhanced ability of cancer cells to repair anticancer drug-induced DNA damage (MOC-4), and decreased expression/function of pro-apoptotic factors or up-regulation of anti-apoptotic genes (MOC-5). Two major goals of modern pharmacology aimed at overcoming this situation are the prediction of a lack of response to chemotherapy and the identification of the underlying mechanisms accounting for primary or acquired refractoriness to anticancer drugs. These are important issues if we are to select the best pharmacological regime for each patient and develop novel strategies to overcome chemoresistance. The present review reports updated information regarding the mechanisms of chemoresistance (from MOC-1 to MOC-5) in gastric cancer, the advances made in the prediction of the failure of chemotherapeutic treatment, and novel strategies based on gene therapy currently being developed to treat these tumors.

MiR‐876‐3p regulates cisplatin resistance and stem cell‐like properties of gastric cancer cells by targeting TMED3

“…Although GC incidence has declined, it is the second most lethal tumor . Surgery is a standard curative treatment for GC patients, whereas it is often not recommended because most GC cases are usually diagnosed at advanced stage . Chemotherapy, as one of the alternative therapies, achieves only modest results because chemotherapy resistance often occurs.…”

“…7 Surgery is a standard curative treatment for GC patients, whereas it is often not recommended because most GC cases are usually diagnosed at advanced stage. 8 Chemotherapy, as one of the alternative therapies, achieves only modest results because chemotherapy resistance often occurs. Hence, a deeper understanding of the mechanisms of GC development and drug resistance is helpful to yield novel therapies for GC treatment.…”

Curcuminoid EF24 enhances the anti‐tumour activity of Akt inhibitor MK‐2206 through ROS‐mediated endoplasmic reticulum stress and mitochondrial dysfunction in gastric cancer

“…The aetiology of gastric cancer is multifactorial and associated with socio‐economic status, poor dietary habits, helicobacter pylori infection, genetic variations, age and family history (Meitzler et al , ). Chemotherapy is an extremely important therapeutic strategy for advanced gastric cancer; however, chemotherapy resistance is a problem, particularly for patients who have progressive cancer and/or had it reoccur subsequent to their first‐line treatment (Kim and Park, ; Marin et al , ).…”

FAT4 hypermethylation and grade dependent downregulation in gastric adenocarcinoma

“…Considering its silent development and consequent delayed diagnosis, this type of cancer is also one of the most resistant cancers to chemotherapy and sometimes surgery is the only choice of treatment, which is not sufficient with regard to disease development (Marin et al 2016;Park et al 2011;Zhang and Fan 2010). With due consideration of the complications and unknown processes of creation and development of this type of cancer, a better comprehension of molecular mechanisms involved in its development can lead to early diagnosis and proper treatment of this malignant disease.…”