Title:Molecular Mechanism of Resistance to Chemotherapy in Gastric Cancers, the Role of Autophagy
Volume: 21
Issue: 7
Author(s): Liudmila V. Spirina*, Alexandra V. Avgustinovich, Sergey G. Afanas’ev, Olga V. Cheremisina, Maxim Yu. Volkov, Evgeny L. Choynzonov, Alexey K. Gorbunov and Evgeny A. Usynin
Affiliation:
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050,Russian Federation
Keywords:
Molecular diagnosis and therapeutics, chemotherapy, tumor markers, autophagy, anticancer therapy, gastric cancer (GC).
Abstract:
Gastric cancer (GC) is biologically and genetically heterogeneous with complex carcinogenesis
at the molecular level. Despite the application of multiple approaches in the GC treatment, its
5-year survival is poor. A major limitation of anti-cancer drugs application is intrinsic or acquired resistance,
especially to chemotherapeutical agents. It is known that the effectiveness of chemotherapy
remains debatable and varies according to the molecular type of GC. Chemotherapy has an established
role in the management of GC. Perioperative chemotherapy or postoperative chemotherapy is applied
for localized ones. Most of the advanced GC patients have a poor response to treatment and unfavorable
outcomes with standard therapies.
Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies.
Through the use of complementary experimental approaches, investigators have revealed that
cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic,
or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation
of MAPK, AKT/mTOR, and Wnt/β-catenin signaling pathways that, when co-opted, enable cancer
cells to survive drug treatments. We have summarized the mechanisms of resistance development
to cisplatin, 5-fluorouracil, and multidrug resistance in the GC management. The complexity of molecular
targets and components of signaling cascades altered in the resistance development results in
the absence of significant benefits in GC treatment, and its efficacy remains low. The universal process
responsible for the failure in the multimodal approach in GC treatment is autophagy. Its dual role
in oncogenesis is the most unexplored issue. We have discussed the possible mechanism of autophagy
regulation upon the action of endogenous factors and drugs. The experimental data obtained in the cultured
GC cells need further verification. To overcome the cancer resistance and to prevent autophagy
as the main reason of ineffective treatment, it is suggested the concept of the direct influence of autophagy
molecular markers followed by the standard chemotherapy. Dozen of studies have focused on
finding the rationale for the benefits of such complex therapy. The perspectives in the molecular-based
management of GC are associated with the development of molecular markers predicting the protective
autophagy initiation and search for novel targets of effective anticancer therapy.
