Breast cancer is the most common cancer in women and the second-leading cause of cancer-related death in women worldwide. Despite progresses in the treatment of early stage breast cancer, approximately one third of patients will develop metastatic breast cancer (MBC). According to the National Cancer Institute, in USA, the estimated new cases and deaths from breast cancer in 2013 would be 232,340 and 39,620 respectively.

Approximately 20%–30% of breast cancers exhibit increased expression of human epidermal growth factor receptor 2 (HER-2/neu) caused by amplification of the erb-B2 oncogene. Breast cancers with elevated HER-2 expression are known as HER2-positive cancers. HER-2-positive breast cancers are more aggressive than other breast cancers. Patients with these tumors have a poorer prognosis and decreased chance of survival compared with patients whose tumors do not overexpress HER-2.

describe the imageHER-2 is a 185-kDa orphan transmembrane receptor tyrosine kinase. Dimerization of HER-2 with ligand- bound HER-3 or HER-4 receptor activates signaling pathways inside the cell. Activated HER-2 signaling stimulates cell proliferation and survival via activation of the MAPK and PI3K/Akt/mTOR pathways. Collectively these signaling pathways result in uncontrolled growth of the tumor. Several studies suggested that the overexpression/amplification of HER-2 may lead to the development and progression of pre-malignant breast disease and also tumor metastasis. Therefore, the association of HER-2 in breast cancer as well as its involvement in tumor aggressiveness makes this receptor an appropriate target for tumor-specific therapies. Several strategies have been developed to inhibit HER-2 signaling. These include a tyrosine kinase inhibitor called lapatinib and a recombinant humanized monoclonal antibody called trastuzumab (Herceptin®).  In this post I will focus only on trastuzumab mediated therapy in breast cancer.  Trastuzumab binds to the extracellular domain of the HER-2 receptor. This inhibits HER-2 signaling via MAPK and PI3K/Akt cascades. In addition, trastuzumab binding also increases membrane localization of the tumor suppressor gene phosphatase and tensin homolog (PTEN), and inhibitor of the PI3K/Aktpathway.

In 1998 trastuzumab was approved for thetreatment of metastatic breast cancer (MBC), and in 2006 for the adjuvant treatment of HER2-overexpressing breast cancer. In early-stage breast cancer, treatment with trastuzumab and a neoadjuvant chemotherapy substantially improves overall survival (OS) and reduces the risk of recurrence, both by 33%. In MBC, trastuzumab treatment in combination with chemotherapy increases the time to progression of the disease by 49% and improves OS by 20%.

However, even though trastuzumab treatment substantially improves outcomes in both early-stage and MBC, both de novo and acquired resistance after initial response was observed. It is suggested that most patients with HER2-positive MBC will eventually develop resistance and have disease progression following trastuzumab treatment.

Several studies reported involvement of multiple factors in resistance to HER2-targeted therapy. These include hindrance to HER-2-trastuzumab binding, signaling through alternative pathways (for e.g. insulin-like growth factor receptor 1, vascular endothelial growth factor receptor) upregulation of signaling pathways downstream of HER-2, increased expression of heat shock protein 90 (HSP90), loss of PTEN and thereby constitutive activation of the PI3K/Akt pathway, and failure to induce an appropriate immune response.

To overcome transtuzumab-resistance, various treatment strategies have been developed. One strategy involves continuation of transtuzumab treatment in combination with a chemotherapeutic agent. In multiple pre-clinical and clinical studies, combination of T DM1 binding resized 600trastuzumab with taxanes docetaxel (Taxotere®) and paclitaxel (Taxol®) exhibited promising response in HER-2–overexpressing metastatic breast cancer.

A new strategy to increase efficacy of trastuzumab has also been developed using antibody-drug conjugate (ADC) technology. The antibody-drug conjugate trantuzumab emtansine (T-DM1, Kadcyla) is consist of trastuzumab bound to maytansinoid (or DM1, a potent microtubule inhibitor) through a nonreducible thioether linkage. T-DM1 binds to HER-2 positive tumor cells and thought to inhibit HER-2 signaling. This ADC also induces body’s immune response to attack cancer cells. Once inside the tumor cells, T-DM1 is designed to kill tumor cells by releasing DM1 which is a potent inhibitor of microtubule assembly, thereby causing cell death inside the cells.

In in vitro and preclinical studies T-DM1 inhibited growth of breast cancer cells which are cross-resistant to trastuzumab. T-DM1 was found well tolerated in phase I clinical study of breast cancer patients who had disease progression with earlier trastuzumab based treatment. In phase II study, increased progression-free survival (PFS) was observed in patients treated with T-DM1 compared to trastuzumab plus doecetaxel treatment. A clinical study published by Verma et al. (2012) reported that T-DM1 significantly prolonged PFS and OS in patients with HER-2 positive MBC previously treated with trastuzumab and a taxane. The most common side effects of T-DM1 treatment include low platelet count, low RBC count, nerve problems, and tiredness. On the basis of clinical efficacy of T-DM1 observed in phase I and II trials, a multicenter phase III trial (also known as EMILIA trial) was performed. This trial also observed increased PFS, reduction of risk of death, and fewer adverse events in T-DM1 treated patients compared to capecitabine plus lapatinib treatment (another first-line treatment option for HER-2positive MBC).

On February 22nd, 2013, the US food and drug administration (FDA) approved T-DM1 (Kadcyla) for the treatment of HER-2 positive MBC that has progressed following treatment with trastuzumab and a taxane.


Suggested reading:

[1] M.F. Barginear, V. John, D.R. Budman, Trastuzumab-DM1: A Clinical Update of the Novel Antibody-Drug Conjugate for HER2-Overexpressing Breast Cancer, Mol Med, 18 (2013) 1473-1479.

[2] M. Barok, M. Tanner, K. Köninki, J. Isola, Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo, Breast Cancer Res, 13 (2011) R46.

[3] M.S. Mohd Sharial, J. Crown, B.T. Hennessy, Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer, Ann Oncol, 23 (2012) 3007-3016.

[4] S. Verma, D. Miles, L. Gianni, I.E. Krop, M. Welslau, J. Baselga, M. Pegram, D.Y. Oh, V. Diéras, E. Guardino, L. Fang, M.W. Lu, S. Olsen, K. Blackwell, E.S. Group, Trastuzumab emtansine for HER2-positive advanced breast cancer, N Engl J Med, 367 (2012) 1783-1791.



Thyroid cancer is a form of tumor growth located within the thyroid gland. It is the most prevalent endocrine malignancy and affects both men and women at any age. During the early stages of the disease, many patients do not experience symptoms. However, as the cancer progresses, symptoms can include a lump or nodule in the front of the neck, hoarseness or difficulty speaking, swollen lymph nodes, difficulty swallowing or breathing, and pain in the throat or neck. There are different types of thyroid cancer: papillary, follicular, medullary, anaplastic, and variants. Among these, differentiated thyroid carcinoma, namely papillary and follicular thyroid carcinoma, makes up about 94% of these cases.

Radioactive iodine (RAI) treatment is given to treat differentiated thyroid carcinoma. The treatment uses a radioactive form of iodine called iodine 131 or I-131. The RAI circulates throughout the body in the bloodstream. Thyroid cancer cells pick up the RAI wherever they are present in the body. The radiation in the iodine then kills the cancer cells. This is a targeted treatment. It doesn’t affect other body cells, because only thyroid cells take up the RAI.  Even though differentiated thyroid cancer is curable, recurrence occurs in 20-40% patients. In about 5% patients with cellular dedifferentiation, the disease develops more aggressive behavior and metastatic growth. This results in tumor resistance to conventional therapy, RAI uptake, and poor prognosis. Resistance to the RAI therapy has been reported to be responsible for a large number of deaths in advanced thyroid carcinomas (papillary and follicular), and represents a major clinical challenge.

Approximately 70% papillary thyroid carcinoma is typically associated with mutations in RET, describe the imageRAS and BRAF oncogenes. In follicular thyroid carcinoma mutations of RAS oncogene in addition to other gene mutations was also observed. Aberrant activities of these oncogenes results in constitutive activation of the MAPK-pathway leading to inhibition of sodium-iodide symporter and thyroid peroxidase genes which participate in iodide uptake and thyroid hormone production respectively. In a pre-clinical study, Chakravarty et al. (2011) showed that mice with poorly differentiating thyroid cancer and overexpressing BRAF (V600E) oncogene failed to uptake RAI. Shutting BRAF activation off or inhibiting the MAPK-pathway with kinase inhibitors targeting BRAF or MEK rendered mice susceptible to a therapeutic dose of RAI. This suggests that inhibition of the MAPK-pathway and its associated protein kinases with the protein kinase inhibitors may facilitate RAI uptake in refractory thyroid cancer patients harboring MAPK-pathway activation.

A pilot clinical study published recently in The New England Journal of Medicine (368;7 February 14, 2013) by  Ho et al. observed that inhibition of the MAPK pathway with MEK inhibitor selumetinib (AZD6244) enhanced RAI uptake in thyroid cancer patients that are CT scanresistant to RAI. Selumetinib is currently in clinical trials for various solid and hematologic malignancies. Among 24 patients screened for the study 5 had NRAS-mutant tumors. All of them showed augmented RAI uptake following treatment with selumetinib; 4 patients exhibited confirmed partial responses (PR) and in 1 patient no disease progression was noted following RAI treatment. No significant levels of toxic effects to selumetinib were observed in this study. Increased RAI uptake and confirmed PR was also observed in 1 patient with BRAF mutation after treatment with selumetinib. However, selumetinib treatment in majority of the patients with BRAF mutations enrolled in this study did not increase RAI uptake up to the threshold level required for therapy. Therefore, further studies are required to understand the differences observed between RAS-mutant and BRAF-mutant tumors.

In addition to the activation of oncogenes, overexpressions of many tyrosine kinase receptors (c-Met, EGF, VEGF etc) has also been reported in dedifferentiated thyroid cancers. The signaling cascades of these receptors cause constitutive activation of both MAPK and PI3K/Akt pathway and thereby disrupting iodine transport and thyroid hormonogenesis. This further suggests that pharmacological abrogation of the MAPK pathway and also PI3K/Akt pathway may be clinically beneficial in RAI-refractory thyroid cancer. Several clinical trials are currently evaluating efficacy of various protein kinase inhibitors (GSK2118436, Sorafenib, Everolimus, Lenvatinib) targeting these pathways to re-sensitize RAI-refractory thyroid carcinomas to radioactive iodine therapy.


Suggested reading:

1. Chakravarty, D., Santos, E., Ryder, M., Knauf, J. A., Liao, X. H., West, B. L., Bollag, G., Kolesnick, R., Thin, T. H., Rosen, N., et al. (2011). Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest 121, 4700-4711.

2. Ho, A. L., Grewal, R. K., Leboeuf, R., Sherman, E. J., Pfister, D. G., Deandreis, D., Pentlow, K. S., Zanzonico, P. B., Haque, S., Gavane, S., et al. (2013). Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368, 623-632.



Overcoming Resistance to Tyrosine Kinase Inhibitors in CML

Chronic myeloid leukemia (CML), a form of slowly progressing blood and bone marrow disease, develops from the neoplastic transformation of hematopoietic stem cells. Transformed hematopoietic stem cells give rise to abnormal white blood cells, also known as leukemia cells. Excessive production of leukemia cells in the body reduce the number of  healthy white blood cells, red blood cells, and platelets in blood and bone marrow resulting our body susceptible to any sort of infection, anemia, or easy bleeding. CML is a triphasic disease characterized by an initial chronic phase that is relatively benign and can last for several years. If untreated, CML progresses to an accelerated phase and/or blast phase, which is associated with increasing symptoms and worsening hematologic parameters. This disease mainly affects adults during or after middle age with a median age of diagnosis at around 65 years. In USA, the annual incidence rate of CML is approximately 4800 cases.

The chief molecular marker involved in the etiology of CML is the BCR-ABL fused gene. The BCR-ABL gene is formed by the fusion of tyrosine kinase gene ABL1 with the BCR gene through reciprocal translocation between chromosomes 9 and 22 during formation of the Philadelphia (Ph) chromosome. The Ph-chromosome is identified in over 95% of patients with CML and represents the genetic hallmark of CML.describe the image Several in vitro studies showed that the tyrosine kinase chimeric protein Bcr-Abl encoded by the BCR-ABL gene is constitutively active in leukemia cells and has oncogenic properties. Bcr-Abl chimeric protein has been found to be associated with genomic instability and thereby suggested to be responsible for progression to advanced phases of CML.

The discovery of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, aimed at inhibiting the tyrosine kinase activation of Bcr-Abl by competitive binding at the ATP-binding site. Imatinib mesylate (Gleevec) was the first tyrosine kinase inhibitor (TKI), approved by the FDA in 2001 for the treatment of chronic phase CML. Patients treated with imatinib exhibited hematological and cytogenetic responses with no disease progression to the advanced phase. However, a significant proportion of patients with CML did not achieve a satisfactory long-term response to imatinib treatment due to acquired resistance which is often caused by the mutation of the BCR-ABL gene. Both in vitro and in vivo studies discovered more than 90 mutations which are suggested to be associated with imatinib-resistance.  Among these mutations the “gate-keeper” mutation T315I appears to be the most common and present in up to 20% patients with CML. This mutation originated as a result of substitution of a threonine (T) residue with isoleucine (I) at amino acid position 315. Crystallographic analysis revealed that BCR-ABL gene mutations cause conformational changes in the ABL-kinase domain that interfere with imatinib binding, resulting in 30 to 40% resistance to imatinib.These findings led to the development of more potent 2nd generation TKIs – dasatinib (Sprycel) or nilotinib (Tasigna™). During clinical studies major cytogenetic response was observed in 35 to 63% of patients treated with dasatinib or nilotinib. In 2010 both TKIs received FDA approval for the treatment of CML patients who are resistant or intolerant to imatinib. Even though dasatinib and nilotinib showed efficacy against a number of imatinib-resistant mutants in CML, they are ineffective against subsets of mutants. In addition, imatinib, dasatinib, and nilotinib failed to show efficacy against the T315I mutant. Therefore, since until recently, the T315I mutation remained a clinical challenge in patients with primary or secondary resistance to dasatinib or nilotinib, whether their disease is newly diagnosed or imatinib-resistant.

A study published in The New England Journal of Medicine (November 29, 2012) by Cortes et al., reported the success of overcoming BCR-ABL T315I mutation mediated resistance to TKIs in CML with a new small-molecule TKI ponatinib (AP24534). In in vitro studies, potent activity of ponatinib was observed against all mutant forms of BCR-ABL (including T315I) at a concentration as low as 40 nM. In the phase I dose-escalation study of ponatinib, Cortes et al. observed complete cytogenetic response and major molecular response in CML patients with non-T315I mutations.describe the image Among chronic-phase CML patients with T315I mutation 100% exhibited hematologic response, 92% had a major cytogenetic response, 75% exhibited complete cytogenetic response, and 67% had a major molecular response. The most common side effects reported in the study include hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. Clinically promising similar results were also observed in the PACE trial, a multicenter, international, single-arm clinical trial of 449 patients with disease that was resistant or intolerant to prior tyrosine kinase inhibitor therapy. On December 14, 2012, the FDA approved ponatinib (Iclusig tablets) for the treatment of adult patients with all phases of CML that are resistant or intolerant to prior tyrosine kinase inhibitor therapy.



1.         O’Hare T, Deininger MW, Eide CA, et al. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011;17:212-221.

2.         Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088.

3.         Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer. 2012;118:3123-3127.

4.         O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.




Inhibition of cell death or apoptosis has been implicated in the chemotherapeutic resistance of tumor cells. TRAIL (tumor-necrosis-factor-related apoptosis inducing ligand; is involved with induction of apoptosis in tumor cells thereby represents an attractive target for the development of anticancer therapy. A type II transmembrane protein and a member of tumor necrosis factor family, TRAIL is expressed in wide range of tissues. Even though it is a membrane protein, TRAIL is also expressed in soluble form. Induction of TRAIL-mediated apoptosis involves binding of TRAIL with its receptor TR1 (also known as death receptor 4, DTRAIL signaling resized 600R4) and TR2 (DR5). TRAIL also binds with two other receptors TR3 and TR4. Unlike TR1 and TR2, these receptors have incomplete death domains. Elevated expression of TR3 and TR4 in normal cells is thereby suggested to protect normal cells from TRAIL-induced death signaling. Induction of apoptotic signaling involves binding of TRAIL to DR4 or DR5. This results in homotrimerization and activation of receptors, enabling the receptors’ death domain to recruit the adaptor protein Fas-associated death domain along with pro-caspase- 8 and pro-caspase- 10. These all together then form the multi-protein death-inducing signaling complex, (DISC). Inside the DISC procaspeses become autoactivated and become caspase-8/10. Activated caspase-8/10 then activates downstream effector caspase-3 or caspase-7. Finally, cleavage of downstream substrates by effector caspases results in DNA fragmentation leading to apoptosis.

Several studies assessed efficacy of TRAIL-based therapies in cancer as a single agent or in combination with other anti-cancer agents. In monotherapy, monoclonal antibodies conatumumab, AMG 655, CS-1008, dulanermin, exatumumab, and mapatumumab exhibited responses in follicular lymphoma, lung adenocarcinoma and in a rare form cancer synovial sarcoma with minimal toxicity. In addition, efficacy of TRAIL-monoclonal antibodies has also been evaluated in combination with anti-cancer agents such as paclitaxel, cisplatin, carboplatin, gemcitabine, histone deacetylase inhibitors, proteosome inhibitors, and kinase inhibitors. However, several cases of adverse effects and toxicities were reported in these studies. In addition, recent TRAIL-based therapies are expensive to produce for clinical applications and may also be limited by endogenous TRAIL level as well as dependency on tumor suppressor gene p53 as a regulator of TRAIL gene transcription. Therefore, studies are required to overcome the shortcoming of current TRAIL-based therapies.

A preclinical study published recently in Science Translational Medicine (Allen et al., 2013) reported that small-molecule drug TRAIL-inducing compound 10 (TIC10) can trigger tumor cell death in a variety of cancers including breast, colon, lung, and also gliobalstoma, a type of brain tumor that is very difficult to treat. The anti-tumor activity of TIC10 is mediated by the activation of TRAIL in Foxo3a dependent manner. In their study, Allen et al. observed significant tumor regression in human colon, triple-negative breast, non-small cell lung, and brain cancer xenograft-bearing mice following single-dose treatment of TIC10. Inactivation of both phosphoinositide 3-kinase/Akt (PI3-K/Akt) and mitoHuman glioblastoma bearing mouse recovered following TIC10 treatment compared to untreated.gen-activated protein kinase (MAPK) pathways was noted following TIC10 treatment in this in vivo study that resulted in translocation of the transcription factor Foxo3a into the nucleus, where Foxo3a induced expression of TRAIL gene to activate apoptosis.

In the pre-clinical study, small-molecule drug TIC10 showed potent anti-tumor activity with limited toxicity through sustained induction of TRAIL even in refractory brain malignancy in a p53-independent manner. This revives the hope of TRAIL-based therapies in cancer. However, clinical trials need to be conducted first in order to confirm safety and efficacy of TIC10 before it can ultimately be used within the clinical setting.



1.         Allen JE, Krigsfeld G, Mayes PA, et al. Dual Inactivation of Akt and ERK by TIC10 Signals Foxo3a Nuclear Translocation, TRAIL Gene Induction, and Potent Antitumor Effects. Sci Transl Med. 2013;5(171):171ra117.

2.         Hellwig CT, Rehm M. TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. Mol Cancer Ther. 2012;11(1):3-13.

3.         Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A, Ford HL. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene. 2012.


Multidrug-Resistance in Cancer: ABC-Transporters

Multidrug-resistance (MDR) is the chief limitation to the success of chemotherapy. According to the National Cancer Institute, multidrug-resistance is a phenomenon where cancer cells adopt to anti-tumor drugs in such a way that makes the drugs less effective. Studies have shown that 40% of all human cancers develop MDR. Deaths due to cancer occur in most of the cases when the tumor metastasizes. Chemotherapy is the only choice of treatment in metastatic cancer, and MDR limits that option.

Cancer one resized 600As shown in Figure 1, tumor cells adopt several mechanisms to evade death induced by anti-tumor agents. These include changes in apoptotic pathways and activation of cell-cycle check points to increase DNA repair. Alternatively, cancer cells develop resistance by increased expression of multidrug-resistant proteins and altered anti-tumor drug transport mechanisms. Members of the ABC transporters (ATP-binding cassette) are known to be associated with this phenomenon, as the human genome express over 48 genes in this transporter family alone. These proteins bind ATP in their ATP binding domain and use the energy to transport various molecules across the cell, thus they are known as ABC proteins. Among these proteins, P-glycoprotein (Pgp, ABCB1), multidrug resistance-associated protein (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are chiefly responsible for drug resistance in tumor cells. Studies are warranted to determine the role of other members of ABC transporters including MRP2, MRP3, MRP4, MRP5, ABCA2 and BSEP in drug-resistance.


cancerPlasma membrane glycoprotein (Pgp) was the first ABC-transporter detected in various cancers exerting resistance to a variety of chemically unrelated cytotoxic agents including anti-tumor drugs such as doxorubicin, vinblastine, ritonavir, indinavir and paclitaxel. It works as an energy-dependent efflux pump and can recognize a wide range of substrates. Even though this protein normally protects us from endogenous and exogenous toxins by transporting them out of the cells, the transporter causes a major problem in the bioavailability of anti-tumor drugs to tumor cells during chemotherapy.

Clinical Significance

Pgp plays an important role in altering the pharmacokinetics of a wide variety of drugs. This efflux pump creates a major physiological barrier in pharmacokinetics of drugs because of its localization at the site of drug absorption and elimination. Tumors with detectable levels of Pgp are 3-4 fold more susceptible to chemotherapeutic failure than Pgp negative tumors. Therefore the role of Pgp in the development of MDR is very significant: it has been used as a potential target for reversing clinical MDR. To overcome Pgp mediated drug resistance several inhibitors are developed and currently in clinical trials which include verapamil, cyclosporin A, quinine, and tamoxifen.

Multidrug Resistance Protein 1 (MRP1)

Like Pgp, MRP1 is also overexpressed in tumor cells and represents a major obstacle to drug delivery. MRP1 is ubiquitiously expressed in the lung, testis, kidney, and peripheral blood mononuclear cells in humans.

Clinical Significance

High levels of expression of MRP1 protein was observed in non-small-cell lung cancer. In breast cancer, there is also a significant expression of this protein which may increase the chance of treatment failure. Studies have also shown that over expression of MRP causes resistance to methotrexate (MTX) and antifoliates such as ZD1694 in colorectal cancer. Development of MRP1 inhibitors is in progress. In preclinical studies, effective inhibition of MRP1 was observed following treatment with MK571 and ethacrynicacid.

Breast Cancer Resistance Protein (BCRP)

BCRP belongs to a novel branch of the ABC-transporter family. The members of this subfamily are about half the size of the full-length ABC transporters, thus known as half-transporters. Overexpression of BCRP was reported in the plasma membrane of  drug-resistant ovary, breast, colon, gastric cancer, and fibrosarcoma cell lines. Even though the normal physiological function of BCRP has not been determined, it is possible that BCRP plays an important role in drug disposition. The overexpression of this protein causes reduced accumulation of chemotherapeutic agents such as mitoxantrone, irinotecan, SN-38, topotectan, and flavopiridol.

Clinical Significance

Since BCRP is expressed in the gastrointestinal tract, it is thought that this protein may affect the bioavailability of the drugs. Its overexpression in several types of cancer makes it a relevant target of strategies aimed at defeating multidrug-resistance. Some of the potent inhibitors of BCRP are Fumitremorgin C, reserpine and tryprostatin A.

Cancer defends itself against chemotherapeutic regimes by several mechanisms including MDR. Therefore, a detail understanding of ABC-transporters mediated drug resistance would help to formulate strategies to overcome this problem. Screening of novel inhibitors of ABC-transporters which are not effluxed by these transporters is currently in progress. One of these drugs, ixabepilone, has been approved in the United States for the treatment of breast cancer patients pretreated with an anti-tumor agent. Ongoing efforts to circumvent MDR also include development of potentially effective alternative strategies (e.g drug delivery using liposomes or nanoparticles, inhibition of expression of MDR associated ABC-transporters using monoclonal antibodies). Promising experimental data on these strategies suggest their potentialily to overcome important causes of MDR to significantly improve cancer treatment.



1.         Türk D, Hall MD, Chu BF, et al. Identification of compounds selectively killing multidrug-resistant cancer cells. Cancer Res. 2009;69(21):8293-8301.

2.         Litman T, Druley TE, Stein WD, Bates SE. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci. 2001;58(7):931-959.

3.         Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48-58.

4.         Gottesman MM, Ludwig J, Xia D, Szakács G. Defeating drug resistance in cancer. Discov Med. 2006;6(31):18-23.

5.         Nobili S, Landini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med Res Rev. 2012;32(6):1220-1262.

Histone Deacetylase Inhibitors: A New Treatment Option in Cancer

Even though cancer is considered as a disease of genetic defects, various studies have shown that epigenetic changes also play an important role in the onset and progression of cancer. Histone acetylation is one of the important epigenetic modifications, and is controlled by two enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs).  HAT transfers the acetyl group from the acetyl co-enzyme A to lysine residues of the histones comprising the core. This is thought to loosen DNA resulting in greater access to DNA for transcription factors and RNA polymerase. HDAC on the other hand, removes the acetyl groups, resulting in the compaction of chromatin thus narrowing access to DNA. Aberrant acetylation of the histone tail by these enzymes is associated with carcinogenesis. Expression patterns of various genes may become changed due to the altered activities of these enzymes.

Histone Deacetylases (HDACs)

HDACs cause transcriptional repression of genes by deacetylating lysine residues on describe the imagehistone tails. HDACs also cause deacetylation of non-histone proteins thus altering the transcriptional activity of p53 (tumor suppressor gene), E2F (transcription factor), c-Myc (transcription factor), nuclear factor kB (NF-kB), hypoxia inducible factor 1α (HIF-1 α), estrogen receptor α, and androgen receptor complexes.

HDACs in Cancer

HDACs are important enzymes in regulating various cellular processes. However, over-expression and abnormal recruitment of HDACs to the promoter region of various tumor suppressor genes may cause tumor initiation and progression. A number of studies have reported a high level of expression of HDACs in various tumors compared to normal cells. Increased expression of HDAC1 was reported in gastric, prostate, colon, and breast carcinomas. Elevated expression of HDAC2 was found in colon cancer.  High levels of expression of HDAC6 were reported in breast cancer. In addition to the over-expression, aberrant recruitment of this enzyme to specific promoter regions may also promote tumor invasion and metastasis. For example, E-cadherin is a transmembrane protein that is found in epithelial cells and plays an important role in cell adhesion. Invasive carcinomas exhibit reduced expression or loss of function of E-cadherin. Recruitment of HDAC1 and HDAC2 to the promoter region of E-cadherin by transcription factor Snail caused reduced expression of E-cadherin.

In addition to histone deacetylation, HDACs also deacetylate non-histone proteins.  For example, mammalian HDAC1, 2, and 3 impair the function of tumor suppressor gene p53. HDACs also alter the transcriptional activity of transcription factor E2F, c-Myc, nuclear factor kB, and HIF-1 α. The chaperone activity of the heat shock protein Hsp90 is regulated by HDAC6. Most of the client proteins of Hsp90 are proteins kinases (c-Raf, MEK, Akt, HER-2) or transcription factors (androgen receptor, progesterone receptor, estrogen receptor) associated with cell proliferation, survival, and signaling.

Histone Deacetylase Inhibitors (HDIs)

With the increasing knowledge of the roles of the HDACs in cancer, efforts have been made to identify potent inhibitors. HDIs identified so far have been shown to induce growth arrest, differentiation, and apoptosis in tumor cells. These inhibitors were found to induce cell cycle regulatory protein p21, apoptotic proteins Bax, and PUMA. HDIs were also able to down-regulate various survival signaling pathways and were able to disrupt the cellular redox state. Therefore, in recent years HDIs have drawn interest as anti-cancer agents. Several HDIs aredescribe the image currently in clinical trials both in monotherapy and in combination therapy with other anti-tumor drugs. A review by Tan et al. (2010) reported that at least 80 clinical trials are underway, testing more than 11 different HDIs in hematologic and solid tumors, including leukemias, lymphomas, and multiple myeloma, lung, breast, pancreas, renal, and bladder cancers, melanoma, glioblastoma. To date, most of the responses using HDIs as single agents were observed in advanced hematologic tumors and few were observed in solid tumors. In 2006, HDI vorinostat (suberoylanilide hydroxamic acid, SAHA) was approved by the Food and Drug Administration (FDA, USA) for the treatment of relapsed and refractory cutaneous T-cell lymphoma CTCL. In November, 2009, the FDA also approved another HDI romidepsin (depsipeptide) for the treatment of CTCL, and in 2011 for the treatment of peripheral T-cell lymphoma patients who have already received prior therapy.

Even though HDIs have shown anti-tumor activity across a broad variety of hematologic and solid tumors in the clinical trials, only a portion of patients with a given diagnosis showed therapeutic response. Therefore, a detailed understanding of the mechanisms of action, as well as mechanisms of resistance, of HDIs would help to identify markers and formulate strategies which may enhance the efficacy of HDIs in the clinic.

Further reading:

1. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287-299.

2. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27(32):5459-5468.

3. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol. 2007;1(1):19-25.

4. Shankar S, Srivastava RK. Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. Adv Exp Med Biol. 2008;615:261-298.

5. Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010;3:5.