Abstract
Cancer cells utilise several mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm, and epigenetic regulation by microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced, and the cancer cells may have acquired drug resistance. This review summarises the main mechanisms involved in cisplatin resistance and interactions between cisplatin-resistant cancer cells and the tumour microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin-resistant non-small cell lung cancer (NSCLC) cellular model using the GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly dysregulated TP53, MDM2, and CDKN1A genes as they encode the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis.
Highlights
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Recent studies showed that the lung cancer cell line, Calu-1, which is moderately resistant to cisplatin, exhibited an elevated level of NER factors, participating in DNA repair including XPA, XPC-hHR23B, XPG, ERCC1-XPF, TFIIH, proliferating cell nuclear antigen (PCNA), and DNA ligase [33]
34% of patients with non-small cell lung cancer (NSCLC) have a mutation of the tumour suppressor gene TP53 that encodes p53 protein, which has been associated with frequent smoking [52]
Summary
Lung cancer continues to be the primary cause of cancer deaths in both men and women, being the most common cancer type for men, constituting 22% of total cancer incidence, and the third most common in women, in whom it represents 8.4% total cancer incidence after breast and colorectal cancers [1,2,3]. About 2.1 million new lung cancer cases were diagnosed worldwide in 2018, which accounts for 11.6% of the world’s total cancer incidence. Lung cancer mortality amounted to 1.8 million in 2018, accounting for 18.4% of cancer deaths [3]. The five-year survival index for early-stage lung cancers exceeds 50% [4]. This high mortality is primarily because only 15% of these cancers are discovered in the early stages; despite the presence of advanced modalities for treatment, most cancers are diagnosed at an advanced stage, and the overall five-year survival rate is only about 15% [4,5]
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