Encyclopedia of Cancer, Springer-Verlag Berlin Heidelberg, 2015
Chemoresistance; Resistance to chemotherapy
Drug resistance refers to the biochemical mechanisms by which cancer cells fail to respond to chemotherapy, such that there is growth of cancer despite therapy. Drug resistance is a major obstacle for the successful treatment of many cancers.
Based on the nature of drug resistance, there are mainly two classes of drug resistance, de novo and acquired resistance. De novo drug resistance means that resistance is present before drug exposure and selection, while acquired drug resistance occurs after prolonged drug treatment and cancer cells develop several derangements to overcome the toxic effect of chemotherapy. De novo resistance may contribute to the failure to eradicate residual minimal disease and facilitate the development of acquired resistance.
De novo drug resistance
To date, several different forms of de novo resistance have been described. One of these forms derives from the mutations in some genes or their downstream signaling pathways that are targeted by chemotherapeutic agents. Several studies have shown that oncogenic mutations in the epidermal growth factor receptor (EGFR) signaling pathway, especially those activating extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, such as mutations in KRAS, BRAF, and NRAS, result in de novo clinical resistance to cetuximab-based therapy, which was developed to target EGFR.
Another form of de novo resistance involves the interaction between cancer cells and tumor microenvironment, namely, environment-mediated drug resistance (EMDR). In EMDR, cancer cells are transiently protected from apoptosis induced by the toxicity of chemotherapy. This form of resistance is induced by either soluble factors, including cytokines, chemokines, and growth factors secreted by tumor stroma, or the adhesion of cancer cells to the stromal fibroblast or extracellular matrix (ECM). Soluble factors, such as IL-6 or stromal cell-derived factor 1 (SDF1), have been shown to increase the transcription of antiapoptotic proteins and confer the resistance in cancer cells to apoptosis. Unlike soluble factormediated drug resistance (SFM-DR), cell adhesion-mediated drug resistance (CAM-DR) is mainly mediated by non-transcriptional mechanisms that are not well understood yet. Some studies suggested that CAM-DR involves the proteasomal degradation of proapoptotic proteins in cancer cells triggered by interaction with integrins or ECM components, fibronectin, collagen, and laminin. CAM-DR may also be mediated by inducing redistribution or modulating the activity of apoptosis-related proteins.
Acquired drug resistance
Several mechanisms have been attributed to the development of acquired drug resistance, including altered drug metabolism; increased drug efflux; intracellular changes that overcome the toxic effects of drugs, such as overexpression or mutation of drug targets; reduced cell apoptosis; increased DNA damage repair; and deranged cytoskeleton organization.
Most drugs are metabolized through a two-phase process composed of phase I and phase II reactions. Metabolic enzymes involved in these reactions may determine individual drug response and resistance. Phase I reactions are mainly carried out by cytochrome P450 (CYP450), a superfamily of mixed-function oxidative enzymes. The different expressions and genetic polymorphisms of CYP450 family members are major determinants in the organ-specific and individual variable response to a given chemotherapeutic agent. Phase II reactions, also known as conjugation reactions, involve the formation of conjugates between substances from phase I reaction and glutathione, glucuronic acid, or sulfate catalyzed by glutathione S-transferase (GST), UDP-glucuronosyltransferase, and sulfotransferase, respectively. Unlike phase I reactions, which may either detoxify/inactivate or toxify/activate substrates, phase II reactions usually inactivate the substances. Elevated expression of phase II detoxificating enzymes, especially GST, has been shown to be responsible for resistance to certain drugs, such as alkylating agents.
Increased efflux of chemotherapeutic agents leading to the reduction of intracellular drug concentrations is another well-established mechanism underlying acquired drug resistance, especially multidrug resistance (MDR). The ATP-binding cassette (ABC) transporter superfamily, the largest family of transmembrane proteins, is responsible for ATP-dependent transportation of a variety of xenobiotics, including drugs. There are 7 subfamilies of ABC transporters designated A to G based on DNA sequence and protein structure. In the 1970s, ABCB1 (or MDR1) gene, which encodes the P-glycoprotein (PGP) transporter, was first shown to be induced in cancer cells selected by in vitro culture with anticancer drugs and resulted in multidrug resistance. Thereafter, several other subfamily members of ABC transporters, including ABCC1 (also known as multidrug resistance-associated protein 1 (MRP1)) and ABCG2 (also known as mitoxantrone resistance (MXR) gene or breast cancer resistance protein (BCRP)), have been associated with multidrug resistance. The drug resistance mediated by these subfamily members shows different tissue specificities and drug specificities, probably due to different expression patterns and structural variations. Other ABC transporters may also confer resistance to certain drugs in different cancer cells.
Intracellular changes in drug resistance
Apart from altered drug metabolism and increased drug efflux, some other mechanisms have been identified in cancer cells resistant to the toxic effects of chemotherapeutic agents. In the past several decades, the role of signaling pathways in the initiation and progression of tumors has been extensively studied, and new chemotherapeutic strategies targeting signal transduction from cell surface to nucleus have been developed. Monoclonal antibodies and small molecules targeting receptor tyrosine kinases (RTKs) including EGFR and IGF-1R have been widely used to treat a variety of cancers. But some patients develop resistance to these drugs over time. One major reason is that some receptors activate multiple downstream signaling pathways, and the overlapping or cross talking among these pathways prevents the effect of a given drug targeting one receptor. In addition, compensatory activation of other receptors or mutations in the targeted receptors also contribute to the resistance to targeted therapeutics.
Cell apoptosis plays an important role in cancer treatment as most chemotherapeutic agents aim to induce cell death through different mechanisms. Consequently, drug efficacy depends not only on the damages they cause to cancer cells but also on the cellular response to these damages by triggering apoptotic machinery in cancer cells. The susceptibility of cancer cells to drug-induced apoptosis is determined by the balance between proapoptotic and antiapoptotic signals. Mutations or downregulation of proapoptotic genes, such as p53, PTEN, Apaf-1, and Bcl-2 family members promoting apoptosis, as well as activation or overexpression of pro-survival genes, such as IAPs and antiapoptotic Bcl-2 family members, is frequently associated with drug resistance in many cancers.
The cytotoxic effect of some anticancer drugs, such as alkylating agents and platinum drugs, relies on their ability to cause DNA damage. The response to DNA damage in cells may include DNA repair, damage tolerance, or apoptosis depending on the nature of DNA damage. These different responses have fundamental infiuence on drug resistance. Activation of DNA repair machinery may remove the potentially lethal DNA lesions caused by chemotherapy and confer resistance to these drugs. On the other hand, DNA damage tolerance provides an alternative mechanism for drug resistance. Cancer cells with mismatch repair deficiency, such as loss of MLH1 expression, may fail to recognize the DNA damage and allow cells to tolerate severe DNA damage without activating cell apoptosis, thus conferring drug resistance.
Microtubules are cytoskeletal structures that play important roles in various cellular processes such as cell division and migration and intracellular trafficking. Microtubules are composed of α–β-tubulin heterodimers that undergo dynamic polymerization and depolymerization. Considering the importance of tubulins in cellular functions, a variety of drugs targeting tubulin and microtubules have been developed. Tubulin-binding agents (TBAs) are a class of drugs that can stabilize or destabilize tubulin, cause the delay or block of mitosis progression, and eventually lead to cell death. Mutations in the predominant βI-tubulin isotype or abnormally high expression of other tubulin isotypes, in particular βIIItubulin, has been established to be associated with drug resistance in various cancer types. Microtubule-associated proteins (MAPs), such as Tau, MAP2, and MAP4, can bind to and stabilize microtubules against depolymerization. Aberrant expression of MAPs is also responsible for some resistance to TBAs.
The above-described mechanisms focus on the intracellular changes that cause drug resistance. But we cannot ignore another important issue in chemotherapeutic treatment, especially for solid tumors, the drug penetration. Anticancer drugs must have access to all the cancer cells to exert the most robust effect. However, many drugs have limited distribution in solid tumors because of disorganized vascular network, the composition of ECM, hypoxic environment, excessive drug binding and retention in the microenvironment, cell–cell adhesion, and so on. All these obstacles limit drug effectiveness. Therefore, developing new drug delivery methods and improving drug design to increase penetration are essential to overcome drug resistance and increase therapeutic efficiency.
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