Overcoming resistance in breast cancer.
Multidrug resistance (MDR) is the cause of treatment failure in an estimated 90% of patients with metastatic cancer . In addition, approximately 50% of patients treated with chemotherapy do not benefit from treatment because of MDR . Past therapies that combatted drug resistance have been unsuccessful, and it is critical that we find new molecular targets and drugs that reverse resistance and improve patient outcomes.
Multidrug resistance (MDR) arises when cancer becomes resistant to a wide array of anti-cancer drugs. Some tumours are resistant to chemo- and endocrine therapies from the onset of disease (intrinsic resistance), while others acquire resistance following treatment (extrinsic resistance). Numerous mechanisms at the cellular level have been implicated, including changes to the tumour microenvironment (i.e. pH), increases in DNA repair, modifications to apoptotic pathways and overexpression of oxidising enzymes. Differential expression and mutations to anti-cancer targets such as topoisomerase-II and (3-tubulin have also been observed .
However, the most widely studied mechanism of resistance is the upregulation of ATP-binding cassette (ABC) transporters in tumour cells. ABC transporters are a superfamily of transmembrane proteins that hydrolyse ATP in order to transport ions, sugars, lipids, steroids and drugs across extracellular and intracellular membranes . Representatives of this family are expressed in all phyla where they help to expel toxic compounds (e.g. human blood-brain barrier), maintain osmotic homeostasis, and facilitate nutrient uptake (e.g. bacteria). In cancer cells, ABC transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance protein 2 (MRP2; ABCC2), eliminate intracellular drug load by transporting substrates (including anthracyclines and taxanes) across the plasma membrane and out of the cell--preventing anti-cancer drugs from reaching their cellular targets [4,5]. These ABC transporters are non-specific, and each is capable of transporting a number of functionally and structurally different substrates. In the same vein, most chemotherapy drugs are substrates of multiple ABC transporters.
A meta-analysis conducted in 2005 concluded that P-gp, as measured by western blotting or immunohistochemistry staining, was expressed in 41% of breast tumours . Expression of P-gp is correlated with a poor clinical response following chemotherapy. Thus, ABC transporters were a target of early MDR therapies; and, although ABC inhibitors such as verapamil and FTC successfully reversed drug resistance in vitro, they were less successful in clinical trials because they increased drug toxicity and did not improve patient outcome. However, these initial studies did not require or measure P-gp expression. Future studies that wish to assess the clinical benefit of an ABC inhibitor should ensure that patients express at least one ABC transporter. An alternative approach in reversing ABC-mediated MDR has been to modify P-gp substrates such that they no longer bind to the transporter. However, the large and non-specific binding sites of ABC transporters, necessary for their multidrug function, have made this a difficult challenge to overcome .
Breast cancer stem cells and chemoresistance
In the past decade, a new model for MDR has emerged with the discovery of cancer stem cells (CSC; also known as tumour-initiating cells). Cancer stem cells possess the ability for self-renewal and capacity to differentiate--driving tumour growth. They were first identified in leukaemias, and several cell surface markers (CD44+/CD247ESA+) have been successful in isolating tumour-initiating stem cell-like side populations in both breast tumours and cell lines [7-9]. Cancer stem cells (CSC) are defined by their ability to form non-adherent 3D colonies in serum-free suspension (mammospheres in breast cancer) and to regenerate the heterogeneous tumour in immunodeficient mice . Furthermore, CSCs are highly resistant to radio- and chemotherapy regimens (such as P-gp substrates paclitaxel and doxorubicin) and, like normal stem cells, they express high levels of the detoxifying enzyme aldehyde dehydrogenase (ALDH), and multidrug transporters P-gp and BCRP [11-13]. The cancer stem cell hypothesis suggests that CSCs are intrinsically resistant to anti-cancer drugs, and that, following treatment, CSCs survive and sustain tumour growth .
CSCs comprise a small percentage of the total cell population but, following neoadjuvant chemotherapy, one study found that breast cancer stem cells (BCSCs) accounted for 74% of tumour cells compared to 9% in chemotherapy-naive patients [14,15]. Another study observed an increase in BCSC populations (4.7% to 13.6%) in patients following 12 weeks of anthracycline or taxane chemotherapy . Similarly, Fillmore and Kuperwasser observed that, following treatment of several cell lines with paclitaxel, the proportion of CSCs increased up to 30-fold . It is therefore likely that tumour recurrences, progression, and metastases are, in part, the product of CSCs that survived initial anti-cancer treatments.
An early study following the discovery of BCSCs did not find a correlation between [CD.44.sup.+]/[CD24.sup.-] cell prevalence in tumour samples and clinical outcome . However, subsequent in vitro studies found that tumorigenic BCSCs were not efficiently isolated by these two markers alone, and that a third marker was necessary (lineage, ESA, or ALDH) [9,11]. A study in 2007 profiled the differential expression of mRNA between [CD.44.sup.+]/[CD24.sup.-]/[lineage.sup.low] tumour cells and normal breast-epithelium cells in human breast tumours. The researchers found that patients with tumours expressing the profile associated with the tumorigenic BCSCs had 10-year rates of overall survival and metastasis-free survival of 62% and 54%, respectively. In contrast, patients with tumours not associated with the BCSC profile had overall survival and metastasis-free survival rates of 98% and 82%, respectively . Similarly, Ginestier and colleagues found that high ALDH activity was enough to isolate tumorigenic stem cells in vitro, and that high ALDH activity in breast carcinomas was correlated with poor prognosis . It has become apparent that, in order to treat metastatic and resistant disease and to improve patient outcomes, we will need to find therapies that target CSCs (without targeting normal stem cells) and sensitise them and their resistant derivatives to existing chemotherapy regimens.
Tyrosine kinase inhibitors
Members of the epidermal growth factor receptor (EGFR) family are transmembrane tyrosine kinase receptors that, with the exception of HER2, are activated by extracellular ligands belonging to the epidermal growth factor family (Figure 1). Their activation requires that they form homo- or heterodimers with other EGFRs and trigger a series of intracellular protein kinase signalling pathways that promote cell proliferation, angiogenesis, invasion, metastasis and inhibition of apoptosis . HER2 is thought to play a role by preferentially dimerising with the other members . EGFR family signalling is often overexpressed and misregulated in solid tumours . HER2 is overexpressed in 30% of breast cancers, and is associated with poor prognosis and aggressive disease . Tyrosine kinase inhibitors (TKIs) now play an important role in the treatment of breast and small cell lung cancers. HER2-expressing tumours are targeted with a monoclonal antibody, trastuzumab, but also with a small-molecule dual kinase inhibitor, lapatinib, which also targets HER1/EGFR.
[FIGURE 1 OMITTED]
Lapatinib is both a substrate and inhibitor of P-gp and BCRP. In vitro, lapatinib, in combination with chemotherapy drugs such as doxorubicin and paclitaxel, reversed P-gp- and BCRP-mediated drug resistance in breast cancer cell lines and mouse models . In a Phase III clinical trial, a positive synergistic effect was observed when lapatinib was combined with capecitabine in HER2-positive patients who had progressed following treatment with an anthracycline or taxane regimen . Similarly, a combination of paclitaxel (a P-gp substrate) and lapatinib in HER2-positive MBC and IBC patients increased overall survival rates [26,27]. Although these studies did not measure P-gp or BCRP expression, it is possible that the observed synergy results from lapatinib-mediated P-gp/BCRP inhibition, which prevents drug efflux and increases drug-induced cell death.
Lapatinib may also regulate ABC transporter protein levels. Although one study did not observe a change in protein or mRNA levels, another found that lapatinib upregulated P-gp protein levels and that this did not affect MDR [24,28]. Meanwhile, epidermal growth factor (EGF) downregulated P-gp expression--suggesting that the EGFR/HER2 signalling pathway may regulate P-gp protein synthesis. Inhibiting HER2 may also make cells more vulnerable to drug-induced apoptosis. Clinical studies have universally observed no change in overall survival rates in patients with HER2-negative tumours--indicating that lapatinib also reverses drug resistance by inhibiting HER2 and downstream anti-apoptotic signalling [25-27]. However, an observable synergistic effect could depend on P-gp or BCRP expression in HER2-negative tumours.
Gefitinib is a small-molecule TKI that inhibits EGFR/HER1. It is used in the treatment of non-small cell lung carcinomas, and has been studied in vitro in breast cancer models. Present evidence indicates that it is an inhibitor of P-gp, and a substrate and inhibitor of BCRP. Initial studies indicated that gefitinib reversed P-gp- and BCRP-mediated chemoresistance; however, more recent analyses suggest that gefitinib's effect depends on the dose and timing of treatment [29-31]. When co-administered or pre-incubated for 1 hour before platinum treatment in a resistant ovarian cell line, gefitinib successfully reversed BCRP- and P-gp-mediated resistance to mitoxantrone and doxorubicin, which subsequently accumulated in cells, due to their binding to P-gp or BCRP. However, if resistant cells overexpressing BCRP were exposed to gefitinib for 5 days prior to treatment with SN-38 or doxorubicin, the anti-cancer drugs failed to accumulate. This is probably due to gefitinib's upregulation of BCRP levels, which during short incubation times do not affect drug resistance . A second method of gefitinib-mediated resistance may be the result of decreased EGFR signalling--and inhibition of downstream pathways such as Akt. The Akt pathway regulates the progression through several mitotic checkpoints and upregulates anti-apoptotic proteins--protecting the cell from apoptosis-inducing therapies. EGFR and Akt signalling are often dysregulated in chemoresistant tumours, and their inhibition by gefitinib may resensitise the cell to drug-induced apoptosis .
In mice, gefitinib enhanced oral absorption and reduced clearance of topotecan, and increased the oral bioavailability and anti-tumour activity of irinotecan in HER1-negative tumours [33,34]. However, gefitinib taken in combination with chemoradiation in neck and head cancers resulted in a non-significant clinical benefit. There was no benefit when gefitinib was combined with carboplatin and paclitaxel in non-small lung cell carcinomas [35,36]. However, these trials did not measure or consider P-gp or BCRP expression, and gefitinib was administered as a daily dose prior to the chemotherapy.
Another small-molecule TKI of EGFR, erlotinib, has been shown to mediate BCRP and P-gp resistance in breast cancer cell models . Erlotinib is a P-gp/BCRP substrate at low concentrations and an inhibitor at higher, clinically relevant concentrations [38,39]. However, unlike other TKIs, erlotinib's effect on P-gp-mediated MDR may also depend on the substrate. Erlotinib did not antagonise (but potentiated) P-gp-mediated resistance to mitoxantrone, but sensitised cells to other P-gp substrates including paclitaxel, vincristine and doxorubicin . However, this data was contrary to earlier findings that erlotinib sensitised cells to mitoxantrone in vitro, and the matter remains unresolved . Sunitinib is a multi-target TKI that inhibits vascular endothelial growth receptors 1, 2 and 3, platelet-derived growth factor receptors, stem cell factor, colony-stimulating factor receptor type 1, FMS-like tyrosine kinase-3 receptor and glial cell line-derived neurotrophic factor receptor . It reverses BCRP-mediated drug resistance in breast cancer cell lines, resensitising cells by allowing them to accumulate anti-cancer drugs and BCRP substrates, including topotecan and doxorubicin. Co-incubation of methotrexate (a BCRP substrate) and sunitinib in cells overexpressing BCRP greatly inhibited methotrexate efflux. Unlike lapatinib, sunitinib does not regulate BCRP expression levels, nor did it block the activation of Akt and Erk1/2 in BCRP cell lines--suggesting that sunitinib's reversal effect is independent of the EGFR and its downstream signalling pathways, and instead it directly inhibits BCRP .
Small-molecule tyrosine kinase inhibitors expose cells to anti-cancer drugs because they block ABC transporter efflux. They may also reverse drug resistance by inhibiting anti-apoptotic signalling via their tyrosine kinase receptor. Small-molecule TKIs are also well tolerated by patients. Thus, they have the potential to reverse MDR in women with breast cancer; but their potential benefit will depend on the patients' P-gp/BCRP/HER2 expression and the regimen within which the TKI is administered.
Targeting the PI3K/Akt pathway
Cancer stem cells, like normal stem cells, are resistant to apoptosis because they need to survive to produce differentiated progeny . This resistance to apoptosis also renders CSCs resistant to anti-cancer drugs whose ultimate effect is to trigger apoptosis and cell death.
The PI3K/Akt pathway is a downstream target of the EGFR family and other tyrosine kinase receptors. Once activated by PI3K, Akt1 promotes cell cycle progression, inhibits apoptosis, induces protein synthesis, and triggers mTORC1--promoting cell growth via mitochondrial biogenesis and lipid synthesis [44,45]. In most cancers, aberrant signalling of the Akt/PI3K/mTOR pathways occurs and leads to uncontrolled cell growth and proliferation . Akt protects cells from anti-cancer therapies by inhibiting pro-apoptotic Bcl-2 family members (BAD), p53 and p21 /p27 that would normally trigger apoptosis following drug-induced stress . mTOR (the catalytic subunit of mTORC1 and mTORC2--which mediates cell growth and proliferation, and activates Akt), Akt and the Bcl-2 family, as well as their downstream effectors, are tempting targets for MDR reversal .
MK-2206 is a small-molecule allosteric inhibitor of Akt. In breast cancer cell lines, MK-2206 potentiated drug-resistance if administered prior to docetaxel treatment, but synergistically induced cell death if administered simultaneously or following docetaxel treatment. In ovarian and lung cancer cell models, when MK-2206 was combined with doxorubicin, camptothecin, gemcitabine, 5-FU and carboplatin treatments, a synergistic effect on cell death and growth inhibition was observed. In vivo mouse models corroborated in vitro data, where gemcitabine or carboplatin was administered in tandem with MK-2206, significantly inhibiting tumour growth compared to either drug alone . Currently, several clinical trials are studying the efficacy of MK-2206 and other Akt/mTOR pathway inhibitors as monotherapies for solid tumours.
The decision to trigger apoptosis largely depends on the ratio of anti-apoptotic to pro-apoptotic proteins present in the cell. The Bcl-2 family of proteins contains both pro-apoptotic members (BAX, BAK) and anti-apoptotic proteins (Bcl-2 Bcl-xl, Bcl-w) and plays a key role in the decision to undergo mitochondrial (intrinsic) apoptosis . In vitro, acquired paclitaxel resistance was mediated either by increased anti-apoptotic Bcl-2 proteins or decreased expression of pro-apoptotic Bcl-2 proteins. In cells overexpressing Bcl-2, resistance to taxanes was restored by a Bcl-2, Bcl-xl, Bcl-w pan-inhibitor ABT-737 . In small-cell lung cancer xenograft tumour models, ABT-737 inhibited tumour growth in only one in three when administered as a monotherapy; however, when etoposide was administered with ABT-737, significant decreases in tumour growth were observed . Several inhibitors of anti-apoptotic Bcl-2 family members are in Phase I/II clinical trials as monotherapies or in combination with another targeted therapy (e.g. erlotinib). However, Bcl-2 has also been shown to have anti-proliferative effects in vitro, to be correlated with better overall survival in women with breast cancer, and to be possibly downregulated in endocrine-resistant breast metastases--questioning its utility as a target for anti-tumour therapy and highlighting the importance of other Bcl-2 family members that may be more promising targets [50-52].
Numerous other proteins that mediate apoptosis and cell growth have been implicated in drug resistance and warrant further study including COX-2, an enzyme involved in cell growth, angiogenesis, and prevention of apoptosis. COX-2 inhibition by celecoxib downregulated P-gp, Bcl-2 and Bcl-xl at low doses and prevented the development of doxorubicin resistance in vitro [53,54]. Mouse models corroborate in vitro data, as celecoxib improved the anti-tumour efficacy of doxorubicin .
Future targets and conclusions
Future therapies for overcoming resistance in breast cancer will have to target the most aggressive and intrinsically resistant cells. Therefore, new therapies will have to destroy breast cancer stem cells and their resistant progenitors, but spare normal stem cells that may exhibit similar properties to BCSCs. This means targeting pathways and proteins that are aberrantly expressed in BCSCs, including anti-apoptotic pathways and detoxifying enzymes (ALDH) that render BCSCs resistant to treatment. Most importantly, to ensure BCSC death by new therapies, it will be necessary to target and stop ABC transporters, or to construct anti-cancer drugs that evade efflux.
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Department of Oncology, Imperial College London, UK
Correspondence to: Caroline Adams
Department of Oncology
Imperial College London
7th Floor, MRC Cyclotron Building
Hammersmith Hospital Campus
Du Cane Road, London W12 0NN, UK
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|Title Annotation:||Feature Article|
|Publication:||Advances in Breast Cancer|
|Date:||Sep 1, 2010|
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