Natural and Acquired Resistance to Cancer Therapies

Figure 47-1 Mechanisms of cellular drug resistance.

It is likely that the rate of development of drug-resistant mutants in a cancer varies depending on the nature of the genetic instability of that cancer, the drug mechanism, and the treatment dose and schedule (selection pressure).^{30–32,37,38}In general, the concept of selection for acquired resistance implies that mutations either may preexist as small subpopulations within the cancer or may arise during the course of therapy and eventually manifest themselves as regrowth of tumor. The tumor cell population in newly diagnosed metastatic cancers almost always exceeds 1 billion cells (equivalent to 1 g or cubic centimeter of tumor). Thus, it is very likely that cancers that are intrinsically sensitive to any therapeutic agent will also contain one or more drug-resistant clones. This provides a powerful rationale for both combination drug therapies (to lessen the likelihood of doubly resistant clones) and adjuvant therapies of cancers (to cure patients with micrometastatic disease and lower tumor burdens).

Recent genetic studies have provided new insights into clonal populations and the evolution of resistant variants in clinical cancers.^39–41These studies used DNA sequencing and sampling of multiple tumor sites of primary and metastatic cancers to directly demonstrate heterogeneity within tumors and changes in the distribution of clonal populations after therapies.

Gene amplification, or increase in gene copy number, was first described for the DHFR gene as a mechanism for acquired resistance to methotrexate. ⁴² Amplification of genes is now known to be a prominent feature of the genomic instability of cells and to be a key genetic mechanism involved in oncogenesis (MYC, HER2, EGFR), as well as in drug resistance. It is one of the major mechanisms for increasing the expression of drug-resistance genes, including MDR1/ABCB1.^27,43

Epigenetics and Drug Resistance

In addition to selection of resistant mutants, acquired resistance may develop via epigenetic changes, by induction of resistance gene expression. ⁴⁴ For example, various cellular stresses, including exposure to ionizing radiation and chemotherapies, have been shown to increase expression of the multidrug transporter gene MDR1/ABCB1.^27,45–47These epigenetic mechanisms such as DNA methylation and histone modifications can contribute to heterogeneity in gene expression and also offer the possibility of reversing drug resistance with drugs such as vorinostat and decitabine that target the epigenome.^48–55MicroRNAs are a target for epigenetic regulation that can alter drug resistance. Thus, downregulation of the miR-200 family results in epithelial-to-mesenchymal transition (EMT) and upregulation of tubulin beta-3 (TUBB3), which can confer resistance to taxane drugs. ⁵⁶

Cancer stem cells (CSCs) represent a subset of cells within a cancer that have the capacity for sustained proliferation and that are thought to be primarily responsible for the growth of cancer. CSCs typically have an EMT phenotype and upregulation of many survival mechanisms, including drug transporters and resistance to apoptosis.^57–60

Tumor Stroma, Cell-to-Cell Interactions, and Drug Resistance

The tumor microenvironment and, in particular, interactions of stromal cells with cancer cells have been shown to enhance drug resistance.^61–64The underlying mechanism for this effect is protection from cell death or apoptosis, mediated by both cellular and noncellular components of the tumor microenvironment. These stromal components include cellular adhesion molecules in the extracellular matrix, chemokines such as CSCL12, and integrins. Cross talk between cancer-associated fibroblasts and malignant cells in tumors promotes tumor progression and cell survival in part via cell adhesion to fibronectin. ⁶⁴

Drug Efflux Transporters

There are approximately 50 ABC transporters (ATP-binding cassette membrane proteins) in the human genome.^65–67Defective forms of several of these transporters are causes of human genetic diseases, such as cystic fibrosis and Dubin-Johnson syndrome. ⁶⁵ Several members of the ABC transporter family have the capacity to efflux small molecules, including anticancer drugs, and thus contribute to drug resistance. The major drug-resistance ABC transporter genes include MDR1/ABCB1, several members of the MRP/ABCC subgroup, and ABCG2.^65,67,68

P-glycoprotein (P-gp), the product of the MDR1/ABCB1 gene, is the most prevalent ABC drug-resistance transporter and has been extensively studied.^69–73The protein has a molecular mass of 180 kDa, with 12 transmembrane segments and two intracytoplasmic ATP binding domains (Figure 47-2 ). High-resolution electron microscopy has revealed that the transmembrane segments form a pore, and drug binding sites have been identified within this pore. Access of drugs to the transporter is thought to occur both via the cytoplasm and by diffusion within the membrane. P-gp is a transporter with very broad substrate specificity, including approximately a third of all anticancer drugs, as well as many other drugs used in other areas of medicine. Active efflux of drugs is mediated by conversion of ATP to ADP. Theories regarding the molecular mechanism of drug extrusion include an ATPase-mediated conformational change in the protein producing a “flippase” action, which exposes substrate drugs to the extracellular environment, and a “membrane vacuum cleaner” function in which drugs access the transporter via the bilipid plasma membrane. ⁷⁰ The direct role of P-gp in conferring multidrug resistance has been confirmed by transfection of the gene in cellular models. ⁷²

P-gp is expressed in many normal tissues, where it serves as a barrier to drug absorption (small bowel and colon), a barrier to tissue entry (endothelial cells of the CNS, testis, and placenta), and to facilitate drug excretion (biliary tract of the liver and proximal tubule of the kidney.^4,73It is also highly expressed in cancers derived from these tissues (colorectal, renal) and is one of the constitutive mechanisms of drug resistance in these cancers.

P-gp expression in cancers results in a classical multidrug-resistance phenotype, with high degrees of resistance to the drugs that are transport substrates for the protein. These drug substrates include the anthracyclines (doxorubicin, daunorubicin, idarubicin, and epirubicin), vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), mitoxantrone, and dactinomycin. ⁷⁰ Many newer, targeted drugs such as imatinib are also transport substrates for P-gp. ⁷⁴

Figure 47-2 Structure and mechanism of action of P-glycoprotein (P-gp). (A) Diagram of P-gp showing the 12 transmembrane segments, two nucleotide binding domains (NBDs), and extracellular glycosylation. (B) P-gp forms a central pore and requires ATPase activity to pump drugs out of the cell. (C) Inhibitors of P-gp function prevent drug efflux, resulting in increased intracellular drug accumulation and enhanced killing of multidrug-resistant cells.

The clinical significance of P-gp in drug resistance is supported by evidence that its expression confers an adverse prognosis in many tumor types, including acute myeloid leukemias (AMLs), acute lymphoid leukemias, lymphomas, myeloma, breast and ovarian cancers, and sarcomas.^9,75–81In AML, P-gp is expressed in more than 70% of specimens from patients older than age 60, versus 30% to 40% of patients up to age 60, and its expression correlates with reduced rates of complete remission and shorter survival. ⁸⁰ In breast cancers, P-gp expression occurs in 40% to 50% of specimens and is associated with decreased rates of remission to P-gp substrate drugs (taxanes and anthracyclines). ⁸¹ Selection of multidrug-resistant (MDR) subclones within cancer populations is suggested by evidence that P-gp expression is more frequent in leukemias and breast cancers after patients have relapsed from prior therapy with MDR-related chemotherapy drugs.^80,81

The prevalence and adverse prognostic effects of P-gp in many cancers have led to attempts to reverse MDR by combining chemotherapy with inhibitors of P-gp.^80,82–84These clinical trials to reverse or modulate MDR have used a variety of competitive and noncompetitive inhibitors of P-gp, including verapamil, cyclosporine, quinine, the cyclosporine analog valspodar, and others. In general, these attempts have not resulted in proven clinical benefit. The reasons for these failures are multiple and include the following: inadequate concentrations of MDR-reversing agents because of toxicities to normal tissues, lack of specificity of P-gp inhibition leading to drug interactions and off-target effects, use of an unselected patient population including patients who did not express P-gp, and coexpression of other mechanisms of drug resistance.^80,82–84A particularly problematic issue is the co-inhibition by cyclosporins and other MDR inhibitors of other ABC transporters as well as the mixed-function oxidase CYP 3A4, resulting in the need to reduce doses of chemotherapeutic drugs while attempting to sensitize P-gp–expressing cancer cells.^84–87Despite these issues, cyclosporine has been shown to moderately increase complete remission rates and to significantly prolong survival in a randomized clinical trial in AML.^80,88A more potent and specific inhibitor of P-gp, zosuquidar, has not prolonged survival in AML, although the schedule of administration of the drug in this trial was suboptimal. ⁸⁹

Several members of the MRP or ABCC gene family also function as drug transporters.^68,90–97The MDR-associated protein (the MRP1/ABCC1 gene) confers resistance to anthracyclines, vinca alkaloids, and epipodophyllotoxins and preferentially transports glutathione conjugates of substrate drugs.^{90,91,94–97}In general, MRP1 is not as strongly associated with clinical drug resistance and prognosis as MDR1, and clinical strategies for reversing resistance related to MRP1 have not been developed. The MRP2/ABCC2 gene encodes the canalicular multiple organic anion transporter, which is expressed at high levels in the biliary tract, and transports glucuronide and glutathione conjugates of drugs, including anthracyclines. It plays a role in hepatic excretion of anticancer drugs, but its role in drug resistance is not clear.^92,95Its hereditary deficiency results in the Dubin-Johnson syndrome. ⁶⁸ The transporter encoded by the MRP3/ABCC3 gene confers low-level resistance to epipodophyllotoxins as well as to methotrexate.^68,93MRP4/ABCC4 and MRP5/ABCC5 confer resistance to anionic purines and other nucleotide analogs and their metabolites.^68,98

ABCG2 (BCRP) is another member of the ABC family, implicated in clinical resistance to the anthracenedione drug mitoxantrone and the camptothecins.^99,100This transporter is 72 kDa in size, less than half the size of the ABCB and ABCC subgroups, and is thought to require dimerization for its function. It is variably expressed in AML and is a negative prognostic factor in that disease.^101–103Together with P-gp, ABCG2 is constitutively expressed in both normal hematopoietic and leukemic stem cells^104,105and is a marker of cancer stem cells. ⁶⁰

Polymorphisms in the DNA sequence of ABCB1 and other ABC transporters are being studied for their relationship to drug disposition, efficacy, and toxicities. ⁶⁶ Single-nucleotide polymorphisms of the ABCB1 gene (C1236T, G2677T, and C3435T), which have been associated with altered drug absorption or disposition in some studies, were not found to effect complete remission and survival in patients with AML. ¹⁰⁶ The function and clinical significance of the ABC transporter family in anticancer drug resistance continue to be investigated.

Two membrane proteins involved in the efflux of copper, ATP7A and ATP7B, have been shown to also transport the platinum drugs and contribute to resistance to cisplatin, carboplatin, and oxaliplatin.^107,108

Impaired Drug Uptake

Cellular entry of most anticancer agents is via passive diffusion. However, some drugs are also transported into cells by membrane proteins, and the expression and activity of these proteins are determinants of cellular sensitivity or resistance. Methotrexate enters cells by means of the reduced folate carrier, and decreased expression of this protein results in relative resistance to the drug. ¹⁰⁹ Reduced drug uptake has also been observed in some cells resistant to platinum drugs. ¹¹⁰ The major copper influx transporter, CTR1, been implicated in the regulation of intracellular accumulation of cisplatin, carboplatin, and oxaliplatin. ¹⁰⁷

Mutation or Altered Expression of Molecular Targets

As previously mentioned, the first description of gene amplification as a genetic phenomenon and as a mechanism for acquired drug resistance was the discovery of amplified dihydrofolate reductase (DHFR) genes in a cell line selected by exposure to increasing concentrations of methotrexate. ⁴² Multiple copies of DHFR were identified in extrachromosomal fragments of DNA, termed double minute chromosomes (DMs), in the methotrexate-resistant cells. Resistance in these cells was unstable because DMs were not normally replicated in the absence of drug selection. ¹¹¹ Subsequently, other methotrexate-resistant cells were found to have multiple gene copies of DHFR integrated into the genome, in areas of “homogeneously staining regions,” or HSRs. HSRs are more stable because they are integrated into the genome and included in the normal process of DNA replication.

Several important classes of anticancer drugs (vincas, taxanes, epothilones) act by binding to β tubulins and altering the dynamic instability of microtubules (Figure 47-3 ). ¹¹² Alterations in β tubulins, including mutations and changes in the proportion of β-tubulin isoforms, particularly the class III isoform, have been implicated in resistance to taxanes.^112–115Vinca alkaloids inhibit tubulin polymerization and thus have opposing effects to those of taxanes and epothilones, which stabilize polymerized microtubules. These opposing mechanisms of action may be reflected in reciprocal effects of changes in tubulin content or isotype expression on vinca and taxane sensitivities, with resistance to one class of drugs accompanied by increased sensitivity to the other. ¹¹² Although mutations in β-tubulin that alter taxane binding have been found to confer resistance in cellular models, such mutations have not been found in various human cancer clinical specimens.^116,117

The microtubule binding protein, MAP-Tau, binds to a site on β-tubulin overlapping with taxanes and affects microtubule dynamic instability. Its expression has been associated with resistance to the taxane drug paclitaxel in breast cancer specimens.^118,119Other mechanisms of resistance to antitubulin drugs include the P-gp transporter (for taxanes and vincas), ⁸¹ the cell spindle checkpoint control pathway, ¹²⁰ and regulation of programmed cell death or apoptosis.^112,121

The epothilones are a new class of antitubulin cytotoxic drugs whose binding site on tubulins overlaps with the taxanes. ¹²² In contrast to taxanes, epothilones are not transport substrates for P-gp and therefore have potential antitumor efficacy in cancers that are multidrug resistant because of P-gp expression.^122,123However, they are likely to share some of the target-related mechanisms of resistance to taxanes, such as factors that affect microtubule dynamicity and regulation of apoptosis.

Topoisomerase I and II are drug targets for camptothecin and epipodophyllotoxin drugs, respectively, and mutations or altered expression of these enzymes have been shown to cause cellular resistance to these drugs.^33,124–129Because drug-induced DNA breakage is proportional to the amount of topoisomerase II enzyme, decreased enzyme content is associated with resistance, and higher enzyme content with drug sensitivity.^33,125,128

Alteration of drug targets is an important mechanism of resistance for new, targeted drugs, such as the tyrosine kinase inhibitors (Figure 47-4 ).^74,130For the drug imatinib, an inhibitor of the fusion oncoprotein gene BCR/ABL, point mutations in the kinase domain of its target are a major mechanism of acquired resistance in chronic myeloid leukemias (CMLs). ¹³¹ More than 30 such mutations that confer resistance to imatinib have been identified. Because resistance to imatinib occurs at a rate of around 3% of patients per year of drug therapy, such mutations occur relatively infrequently. The drug dasatinib, a potent inhibitor of the BCR/ABL kinase, has been shown to inhibit almost all of these mutant kinases and to produce remissions in imatinib-resistant CML. ¹³¹ One BCR/ABL mutant, T351I, remains resistant to both imatinib and dasatinib, although other new drugs are being developed for this double-resistant mutation. BCR/ABL gene amplification can also result in resistance to the kinase inhibitors in CML. ¹³²

Figure 47-3 Mechanism of action of tubulin polymerizing and microtubule-stabilizing drugs.

Intracellular Redistribution of Drug

Intracellular drug sequestration of anthracyclines has been observed in cellular models with high expression of the major vault protein (MVP), also known as LRP. ¹³³ Vaults are barrel-like cytoplasmic organelles with a molecular mass of 13 MDa, which are thought to function in intracellular transport. In addition to high expression of MVP in some cellular models of drug resistance, this protein is variably expressed in acute myeloid leukemias and may be a factor in clinical drug resistance in that disease. ¹³⁴

Detoxification of Drug or Intermediate Drug Product

Metabolic inactivation of drugs is a mechanism of resistance to many agents. Thus, cytidine deaminase activity can result in resistance to cytarabine. ¹³⁵ Dihydropyrimidine dehydrogenase catabolism of 5-fluorouracil is a determinant of activity of that agent. ¹³⁶

The DNA-binding glycopeptide drug bleomycin is inactivated by an aminopeptidase termed bleomycin hydrolase. ¹³⁷ Most cancers are resistant to bleomycin and have high levels of this enzyme, whereas sensitive tumors (germ cell cancers, lymphomas, squamous carcinomas) have low levels. Similarly, most normal tissues have high levels of bleomycin hydrolase, but the two major sites of toxicity, lung and skin, express low levels. ¹³⁷

For electrophilic DNA alkylating agents and platinum drugs, detoxification via nucleophilic sulfur-containing compounds is an important class of resistance pathways. ¹⁰⁸ Glutathione reductases are an important class of detoxifying enzymes that can generate resistance to such drugs by conjugation with glutathione.^138–148Moreover, as previously noted, some members of the MRP family of transporters can efflux glutathione conjugates of cytotoxic drugs, so that metabolic detoxification is coupled to outward transport of toxins.^68,95,97

Figure 47-4 Cellular pathways of programmed cell death, or apoptosis.

Enhanced DNA Repair

DNA repair pathways are important determinants of response to alkylating agents and platinum drugs.^{108,149–152}Nucleotide excision repair (NER) is a complex, highly regulated process involving more than 30 proteins. Moreover, two general pathways are involved: global genomic NER, which repairs damage in transcriptionally silent areas, and transcription-coupled NER, which repairs damage to the actively transcribed DNA strand. The steps in NER include recognition of the damaged DNA, DNA unwinding, incision, degradation, polymerization, and ligation. ¹⁵¹ Evidence for the role of many DNA repair genes in response to both DNA-damaging drug and ionizing radiation derives in part from studies of genetic defects such as ataxia telangiectasia, xeroderma pigmentosum, and Bloom syndrome, in which hypersensitivity to DNA-damaging agents has been observed.

Among the many genes involved in NER, recent attention has focused on ERCC1. High expression of the DNA excision repair gene ERCC1, which is involved in repair of DNA adducts from alkylating agents and platinum drugs, has been shown to correlate with adverse outcomes in patients with advanced-stage non–small-cell lung cancers treated with cisplatin-based chemotherapy. ¹⁵³ In earlier stages of lung cancer, patients whose tumors did not express ERCC1 benefited significantly from cisplatin adjuvant chemotherapy, whereas patients whose tumors expressed ERCC1 did not benefit from the chemotherapy. ¹⁵⁴ Paradoxically, high expression of ERCC1 was found to be a favorable prognostic factor for survival in patients with early stages of lung cancer, in the absence of adjuvant chemotherapy.^154–156

O6-Methylguanyl-methyl-transferase (MGMT) is particularly important in resistance to the nitrosourea carmustine and the DNA-methylating agent temozolomide.^149,151MGMT has been identified as a key factor in clinical outcomes in brain tumors, and drugs to deplete MGMT are being developed as potential therapeutic approaches to modulate drug resistance. ¹⁴⁹

Decreased Drug Activation

Most antimetabolite drugs generally require metabolic activation to generate their active nucleoside or nucleotide moiety, via kinases and phosphoribosyl transferases. ¹⁵⁷ Thus, for cytarabine, generation of ara-dCTP levels intracellularly is an important determinant of antitumor efficacy. ¹⁵⁷ In the case of 5-fluorouracil, activation of the drug requires formation of 5-fluorodeoxyuridine monophosphate (FdUMP). ¹⁵⁷ In addition, optimal inhibition of thymidylate synthase by 5-fluorouracil depends in part on intracellular levels of the cofactor 5,10-methylene tetrahydrofolate. ¹⁵⁸

The oxazaphosphorine mustards (cyclophosphamide and ifosfamide) are prodrugs that are activated predominantly in liver tissue by mixed function oxidases (CYP enzymes). ¹⁵⁰ Although the major mechanisms of resistance to these drugs are thought to be inactivation of alkylating metabolites by thiol compounds, as well as DNA repair mechanisms, variable levels of mixed function oxidase activity within cancers may also be a determinant of their activity.

Altered Pathways for Programmed Cell Death (Apoptosis)

Pathways for the regulation of programmed cell death or apoptosis are important both in oncogenesis and as determinants of response to cancer therapies (Figure 47-5 ).^12–25BCL2 is oncogenic in many B-cell lymphomas, where its expression is upregulated by chromosomal translocations and other mechanisms. It also functions to protect cells from apoptosis after radiation, glucocorticoids, and chemotherapies.^13,14,25The BCLX gene has long and short forms, encoding the proteins bcl-xL and bcl-xS, which serve to inhibit and promote apoptosis, respectively. ²⁴ Both the BCL-2 and the inhibitor of apoptosis (IAP or BIRC) families of regulators of cell death are currently being explored as targets to sensitize drug-resistant cancer cells to chemotherapies.^159,160

The relationship between oncogenesis and drug sensitivity or resistance is also exemplified by the p53 pathway, which is mutated in the majority of human cancers. Normal p53 function is essential for the efficient functioning of the mitochondrially mediated apoptotic pathway, particularly in response to DNA-damaging agents, including ionizing radiation and many chemotherapeutic drugs, such as alkylating agents, platinums, anthracyclines, and topoisomerase inhibitors.^12,15,22,23

Individualization of Therapy Based on Predictive Multigenic Markers

Knowledge about mechanisms of drug resistance, molecular targets of drugs, and signaling pathways related to treatments is enabling more precise predictive molecular testing of drug efficacy. ¹⁰ Historically, such approaches were pioneered in the treatment of breast cancer by the use of hormone receptor measurements to guide hormonal therapy and testing for overexpression or amplification of the HER2 gene to identify breast cancer patients for trastuzumab therapy. The ability to determine genome-wide expression by microarray analysis has resulted in the identification of candidate gene profiles that are associated with remissions to drugs or drug combinations.^161,162Such approaches may lead to increasing individualization of therapy with the use of genomic or proteomic panels of predictive markers, but prospective validation of such markers in clinical trials has been difficult.

Figure 47-5 Structure of the fusion oncoprotein BCR/ABL, depicting the point mutations that result in resistance to imatinib in chronic myeloid leukemias.

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