Antineoplastic resistance
Cancer cells are constantly using a variety of tools, involving genes, proteins, and altered pathways, to ensure their survival against antineoplastic drugs.
In breast cancer models of the mouse the immune microenvironment affects susceptibility to neoadjuvant chemotherapy.
In breast cancer, particularly in the triple-negative subtype, immune checkpoint blockade has been used successfully in metastatic cases and neoadjuvant therapy.
[10] Determining areas of gene amplification in cells from cancer patients has huge clinical implications.
This can occur with replication fork barriers, proteins such as PTIP, CHD4 and PARP1, which are normally cleared by the cell's DNA damage sensors, surveyors, and responders BRCA1 and BRCA2.
In cancer cells, where normal regulation of gene expression breaks down, the oncogenes are activated via hypomethylation and tumor suppressors are silenced via hypermethylation.
[12] Studies on cancer cell lines have shown that hypomethylation (loss of methylation) of the MDR1 gene promoter caused overexpression and the multidrug resistance.
Experiments in different drug resistant cell lines and patient DNA revealed gene rearrangements which had initiated the activation or overexpression of MDR1.
In colorectal cancer cells, inhibition of NF-κB or MDR1 caused increased apoptosis in response to a chemotherapeutic agent.
Platinum-based chemotherapies, such as cisplatin, target tumour cells by cross-linking their DNA strands, causing mutation and damage.
[27] Upregulated expression of Bcl-2 in leukemic cells (non-Hodgkin's lymphoma) resulted in decreased levels of apoptosis in response to chemotherapeutic agents, as Bcl-2 is a pro-survival oncogene.
[29] Another line of therapeutics used for treating breast cancer is targeting of kinases like human epidermal growth factor receptor 2 (HER2) from the EGFR family.
[12] Treatment of chronic myeloid leukemia (CML) involves a tyrosine kinase inhibitor that targets the BCR/ABL fusion gene called imatinib.
Mutant enzymes have also been reported in patient leukemic cells, as well as mutations in other cancers that confer resistance to topoisomerase inhibitors.
[34] Rapid sequencing technologies can identify genetic markers for treatment sensitivity and potential resistance.
Inhibition of the MDR genes could result in sensitization of cells to therapeutics and a decrease in antineoplastic resistance.
Reversin 121 (R121) is a high-affinity peptide for MDR, and use of R121 as a treatment for pancreatic cancer cells results in increased chemosensitivity and decreased proliferation.
Expression of mutated TP53 causes defects in the apoptotic pathway, allowing cancerous cells to avoid death.
[38] In ovarian cancer, the ATP7B gene encodes for a copper efflux transporter, found to be upregulated in cisplatin-resistant cell lines and tumors.
