مقالات پذیرفته شده در ششمین کنگره بین المللی زیست پزشکی
A Review of the Mechanisms of Resistance to MAPK Signaling Pathway Inhibitor Drugs in Cancer Therapy
A Review of the Mechanisms of Resistance to MAPK Signaling Pathway Inhibitor Drugs in Cancer Therapy
Ali Barani,1Kamyar Beikverdi,2Seyed-Morteza Javadirad,3,*
1. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan 2. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan 3. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan
Introduction: Mitogen-activated protein kinase (MAPK) pathways regulate all aspects of life and are frequently altered in disease. MAPK pathways are three-kinase cascades in which the most upstream kinase (MAPKKK) responds to extracellular and intracellular signals and directly phosphorylates the middle kinase (MAPKK). The MAPKK exclusively phosphorylates and activates a MAPK, which typically has a large number of substrates that carry out specific cell fate decisions appropriate to the input signal. Cancer and drugs targeting the RAS-RAF-MEK-ERK pathway have made the most progress. Extensive research has been conducted on drugs that target this pathway, as well as mechanisms of sensitivity and resistance.
Methods: To find relevant articles, a search was conducted using the Google Scholar web search engine and the PubMed database. The keywords "cancer", "drug resistance “and” MAPK pathway" were used, and several articles were chosen for further investigation.
Results: Resistance to MAPK pathway inhibitor drugs can develop in a variety of ways, depending on cell type and cancer type, according to research papers on the subject. The RAS-RAF-MEK-ERK pathway is altered in nearly 40% of human cancers, primarily due to mutations in BRAF and its upstream activator RAS. MEK inhibitor drugs were the first to be developed, but despite their high potency, when administered alone, they produced disappointing clinical results. This was caused by the pathway's negative feedback amplifier property, which works to stabilize the output by influencing RAF. As a result, the combination of RAF and MEK inhibitors has become common in the treatment of certain types of cancer. Resistance to RAF and MEK inhibitors, on the other hand, leads to the discovery of other escape mechanisms, namely the role of adaptive network responses such as the JNK and p38 pathways. JNK is a cell death modulator that shares several substrates with the ERK pathway. The CJUN transcription factor, one of these shared substrates, promotes cell survival in cells treated with the RAF inhibitor vemurafenib. Combining a JNK inhibitor with vemurafenib clearly induces apoptosis. JNK inhibition has been shown to be effective in treating vemurafenib-resistant melanoma cases where JNK works to reactivate the ERK pathway via other pathways, such as PAK (a kinase). The phosphatase PP2AC appears to influence the balance of the p38 and ERK pathways. P38 inhibitors promote cell proliferation in low-proliferation cells. P38 inhibitors promote proliferation in cells with low PP2AC expression by inhibiting ERK, while inducing cell death in cells with high PP2AC expression.
Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, inhibits ERK1/2 activation by the scaffold protein IQ-domain GTPase-activating protein1 (IQGAP1) in pancreatic ductal adenocarcinoma (PDAC) cells. Furthermore, resistance to RAF inhibitors and high glycolytic activity were observed in BRAF V600E and NRAS Q61K mutant cells from melanoma patients. Adding dichloroacetate, a glycolytic suppressor, to vemurafenib broke the drug resistance in these mutant cells.
A number of studies have also suggested that amino acid metabolism may play a role in drug resistance to BRAF inhibitors. Specifically, it was discovered that serine biosynthesis had an effect on vemurafenib resistance.
Conclusion: Although the MAPK signaling pathway is important in many types of cancers and malignancies, making it an appealing target for cancer therapy, resistance to these inhibitory drugs can be achieved through a variety of mechanisms, including the activation of other pathways and metabolic modulators. Understanding this complex, context-dependent network is required for the development of effective drugs. Using computational models may be the key to overcoming this barrier.