Dear Ammar,

The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energy-dependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms probably play an important role in acquired anticancer drug resistance. Drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters.

Overexpression of p-glycoprotein is also largely responsible for drug efflux out of the cancer cell and cause MDR.

For a comprehensive reading I am sharing a combined pdf file of some important articles in that area.

Hope that helps.

Dear Ammar,

The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energy-dependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms probably play an important role in acquired anticancer drug resistance. Drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters.

Overexpression of p-glycoprotein is also largely responsible for drug efflux out of the cancer cell and cause MDR.

For a comprehensive reading I am sharing a combined pdf file of some important articles in that area.

Hope that helps.

Knowing the mechanisms of drug resistance and targeting the drug resistance cancer may not be simple reversible process. ABC transporters may cause drug resistance but simply targeting ABC using drugs does not work. You have to apply other approach.

Have a look at the attached file. You may get some input.

MULTIDRUG RESISTANCE (MDR) MECHANISMS: A REVIEW

Given some fine contributions above along with a rich literature on multidrug resistance (MDR) in oncology, I will confine myself, from a recent review of these issues I conducted, to clarifying (1) some of the nuances involved in both the mechanisms of resistance, and of (2) overcoming resistance with some examples of recent notable successes, and in addition (3) will try to shed some much needed light on the frequent confusions surrounding relapse as true recurrence versus the emergence of a new primary, a matter of some considerable clinical importance. As always, I restrict the scope of evidence considered to only high-level evidence (ex vivo and above, critically human clinical data). Although I cover traditional areas, I am most concerned with the frontier edge of resistance strategies such as those surrounding Cancer Stem Cells (CSCs), microRNAs (miRNAs), and nanomedicine. (Note: for the antiHER2 agent trastuzumab (Herceptin) used in HER2-positive breast cancer, please consult my own paper, available on my ResearchGate profile [43].

MULTIPLE MECHANISMS OF RESISTANCE AND SOME BREAKTHROUGHS

Drug resistance can be mediated by a number of different mechanisms (with different drugs and drug classes exhibiting different resistance mechanisms), principally:

1. INCREASE IN THE ACTIVITY OF ATP-DEPENDENT EFFLUX PUMPS

These are increases in efflux pumps such as adenosine-triphosphate- (ATP-) dependent transporters, in particular via overexpression of ATP-binding cassette (ABC) transporter proteins such as P-glycoprotein (P-gp), multidrug-resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP) - resulting in reduced intracellular drug concentrations. Agents that are substrates for P-gp and hence commonly associated with this type of resistance include anthracyclines, taxanes, antimetabolites, and vinca alkaloids (such as doxorubicin, daunorubicin, vinblastine, vincristine and paclitaxel) [1,2]. Note that MRP1 has been shown to confer resistance to anthracyclines and vinca alkaloids, but not taxanes [3].

In a meta-analysis of 31 breast cancer clinical trials, P-gp overexpression was associated with 3-fold increased risk of failure to respond to chemotherapy, P-gp expression was observed to increase after chemotherapy exposure [4]. Numerous efflux pump inhibitors, one of the best studied being tariquidar, a potent, specific, noncompetitive inhibitor of P-glycoprotein, which showed modest objective response in NSCLC and ovarian cancer [29] (and clinical activity to restore sensitivity to anthracycline or taxane chemotherapy in breast cancer).

2. REDUCTION OF CELLULAR DRUG UPTAKE:

Water-soluble drugs may attach to transporters carrying nutrients and therefore fail to accumulate within the cell. Resistance to drugs like cisplatin, and 5-FU is mediated by this mechanism [5].

3. CYTOCHROME P450 HEPATIC ENZYME SYSTEM:

Activation of regulated detoxifying systems such as the cytochrome P450 mixed function oxidases can lead to drug resistance in dozens of CYP-mediated agents by well-known pharmacokinetic mechanisms.

4. INCREASED DNA REPAIR:

Activation of mechanisms that repair drug-induced DNA damage are criticallly involved in acquired resistance. For example, it is known that platinum resistance is related to expression of DNA excision repair proteins, in particular ERCC-1.

As a practical example, a recent clinical trial [30] in platinum-resistant ovarian and peritoneal carcinoma patients used the 5-FU prodrug, gemcitabine (Gemzar) which is known to modulate ERCC1 nucleotide excision repair activity, and coupled it with cisplatin, to overcome resistance and produce an impressive ~43% objective response (partial and complete) in this refractory population.

5. DYSFUNCTIONAL APOPTOTIC PATHWAYS:

In addition, resistance can result from defective apoptotic pathways - such as the apoptosis-associated protein Bcl-2 - due to (1) malignant transformation [6], (2) a change in the apoptotic pathway during chemotherapy exposure, (3) in particular disruptions in apoptotic signaling pathways that decrease susceptibility to drug-induced cell death [7] including the anti-apoptotic Src pathway, or (4) changes in the cell cycle mechanisms that activate checkpoints and prevent initiation of apoptosis.

The pro-apoptotic Src inhibitor, dasatinib (Sprycel) has just been reported (at SABCS 2013, December) [31] to overcome endocrine resistance and reactivate apoptosis, more than doubling progression-free survival (PFS) in metastatic breast cancer patients.

6. DYSFUNCTION OF TUMOR SUPPRESOR GENES (TSGs):

That is, altered expression of tumor suppressor protein p53 which induces drug resistance. Here we have some positive findings from HDAC/DNMT inhibitors which have shown success in both preclinical and clinical studies, including in the large human clinical ENCORE 301 RCT [21].

7. PI3K/AKT/mTOR PATHWAY ACTIVATION:

Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors (TKIs), radiotherapy (RT), and cytotoxics.

For example, the incorporation of mTOR inhibitors has effectively, and dramatically, countered dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway and overcome numerous classes of drug resistance, especially endocrine resistance [16-20] where everolimus (Afinitor) has produced some of the most exciting recent results in HER2 and endocrine-positive breast cancer.

8. MICRORNAs (miRNAs):

The mechanisms for endocrine resistance are multiple and include deregulation of various components of the estrogen receptor (ER) pathway, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways (such as the HER2 pathway), and dysregulation of miRNA expression has been associated with both preclinical and clinical endocrine therapy resistance, showing that miRNAs are pivotal to understanding the complex biological mechanism of endocrine resistance, and to effectively overcoming it [22].

So in this connection, a high level of miRNA-210 expression was observed to be associated with a higher risk of recurrence compared with lower levels, and miRNA-210 was shown to be associated with a poor clinical outcome in tamoxifen treatment, secondary to its association with endocrine resistance [23]. In addition, an association was demonstrated between high expression levels of, in particular, miRNA-30c and clinical benefit/longer progression-free survival (PFS) [24]. Furthermore, increasing levels of miRNA-26a were observed to be significantly associated with clinical benefit and prolonged time to progression (TTP) in ER-positive patients administered tamoxifen as first-line therapy of metastatic disease [25]. These findings are been further explored and extended in the MIRHO Trial in France (NCT01612871) in endocrine-positive breast cancer, as well as in prostate cancer (NCT01050504), and in a completed trial (results to appear) in lymphoma (NCT01606605), among many others.

9. CANCER STEM CELLS (CSCs):

Numerous reports implicate such cancer stem cells (CSCs) in the acquisition of drug resistance, with stem cell-like subpopulations being generally more refractory to drug treatment [8,9]. These and related studies have called into question the widely described 'hierarchical' model of cancer stem cells, in which the dogma (now effectively challenged) is held that stem cells can only arise from other stem cells, with the contrary demonstration that nonstem cells can spontaneously acquire stem cell properties [10,11], and cancer stem cells that have undergone EMT share properties associated with drug resistance [12,13]. Most intriguing is the fact that epithelial cells undergoing an EMT can actually acquire stem cell properties [14,15]. Note further that in the CSC model, rare populations of cancer stem cells possess tumor-initiating properties [26] and diverge from normal tissue stem cells through dysregulation of self-renewal pathways, enabling resistance via (1) modulation of molecular mechanisms, especially such as increased efficiency of DNA repair due to enhanced DNA damage response, (2) changes in cell cycle parameters, (3) overexpression of anti-apoptotic proteins or drug transporters (via ABC transporter expression or aldehyde dehydrogenase (ALDH) activity), and (4) B-cell lymphoma-2 (BCL2) related chemoresistance; and (5) by what I may call cycle-hiding due to their quiescent nature: namely, although the cell population is present it is difficult to target using traditional chemotherapies many (but not all of which) of which depend on active cell cycling [27], and activation of key signaling pathways [28].

Many agents can inhibit cancer stem cell (CSC) activity, including the anti--diabetic agent and mTOR inhibitor metformin, and we are awaiting the results of the recently completed Tufts Medical Center trial of metformin on colorectal cancer stem cells (CRC-CSCs) and nanomedicine is also showing considerable promise in this arena, as such in the use of "nanoshell technology" in the form of nanoparticle-mediated hyperthermia (NMT), under the trade name Aurolase, against CSC-harboring breast tumors (in clinical trial), as well as the use of a polymer-encapsulated curcumin nanoparticle formulation (NanoCurc) for the treatment of brain tumor stem cells, as well as other new and emerging nanoparticle platforms including liposomes, micelles, nanoemulsions, polymers, quantum dots, gold, iron-oxide, and dendrimers, among other exciting CSC-modulating strategies on the frontier-edge of research.

10. RELAPSE

Studies have shown that more than one-third of patients with metastatic breast cancer fail respond to first-line anthracyclines or taxanes and the development of drug resistance accounts for failure of treatment leading to death in more than 90% of patients with MBC [32], affecting all classes of agents (chemotherapeutics/cytotoxics, endocrine/hormonal, biological/targeted) [33]. It is important to understand that the time to relapse after initial chemotherapy is generally empirically divided into 6-month blocks, with refractory tumors demonstrating progression during or immediately following chemotherapy, and when the disease-free interval is brief (less than 6 - at most 12 months), it appears that acquired or intrinsic drug resistance is majorly responsible for tumor progression [34].

DISTINGUISHING RELAPSE AS TRUE RECURRENCE VERSUS NEW PRIMARY

It should be recognized that a significant portion of breast cancer patients who experience an ipsilateral relapse following conservative surgery and radiation therapy actually have new primary tumors rather than true local recurrences, and true recurrence and new primary tumor relapses have dramatically different natural histories, different prognoses, and consequently different implications for therapeutic management [35]. In this connection, we note that its been decisively demonstrated that patients with new primaries have better survival rates - in terms of overall survival (OS), distant disease-free survival (DDFS) and metastasis-free survival (MFS), with patients with a new primary having a 10- year overall survival of hovering around 90% compared to just above 60% for cases of true recurrence - than those with true recurrence, and this is true across malignancies, that new primaries systematically exhibit better prognoses and significantly improved survival outcomes than true recurrences, and new primaries - rather than true recurrences, account for a significant proportion of late relapses being de novo occurrences of breast carcinoma (true recurrences tend to occur earlier and are more highly associated with metastatic potential, stemming largely from residual surviving tumor clonogens) [36-42], so in answer to Robert Eibl's shrewd question re late relapse, although this can of course occur, the data suggests that late relapses are far more likely to be new primaries and not true recurrences, a prognostically favorable situation, so the discrimination between true recurrence and second primary tumor is of strong implication for optimal patient management.

METHODOLOGY OF THE REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE/MedlinePlus, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health), and scope-qualified Boolean searches submitted to Google Scholar and SLIM, was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations), OpenThesis or Proquest. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 1999;39:361-98.

2. Perez EA. Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Res Treat 2009; 114(2):195-201.

3. Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy 2009; 29(8):954-65.

3. Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy 2009; 29(8):954-65.

4. Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 1997 Jul 2; 89(13):917-31.

5. Shen DW, Goldenberg S, Pastan I, Gottesman MM. Decreased accumulation of [14C]carboplatin in human cisplatin-resistant cells results from reduced energy-dependent uptake. J Cell Physiol. 2000 Apr;183(1):108-16.

6. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993 Sep 24; 74(6):957-67.

7. Liu YY, Han TY, Giuliano AE, Cabot MC. Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 2001; 15(3):719-30.

8. Gupta PB, Onder TT, Jiang G et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell138(4),645–659 (2009).

9. Li X, Lewis MT, Huang J et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst.100(9),672–679 (2008).

10. Chaffer CL, Brueckmann I, Scheel C et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA108(19),7950–7955 (2011).

11. Quintana E, Shackleton M, Foster HR et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell18(5),510–523 (2010).

12. Guo W, Keckesova Z, Donaher JL et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell148(5),1015–1028 (2012).

13. Scheel C, Weinberg RA. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int. J. Cancer129(10),2310–2314 (2011).

14. Mani SA, Guo W, Liao MJ et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell133(4),704–715 (2008).

15. Blick T, Hugo H, Widodo E et al. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44hi/CD24lo/- stem cell phenotype in human breast cancer. J. Mammary Gland Biol. Neoplasia15(2),235–252 (2010).

16. Nahta R, O'Regan RM. Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer 2010; 10 Suppl 3:S72-8.

17. Dragowska WH, Weppler SA, Qadir MA, et al. The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity. BMC Cancer 2011; 11:420.

18. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012 Feb 9; 366(6):520-9.

19. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012 Aug 1; 30(22):2718-24.

20. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012 Feb 9; 366(6):520-9.

21. Yardley DA, Ismail-Khan R, Klein P. Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI). J Clin Oncol 2011; s27:268.

22. Zhou J, Teng R, Wang Q, et al. Endocrine resistance in breast cancer: Current status and a perspective on the roles of miRNAs (Review). Oncol Lett 2013; 6(2):295-30.5.

23. Rothé F, Ignatiadis M, Chaboteaux C, et al: Global microRNA expression profiling identifies MiR-210 associated with tumor proliferation, invasion and poor clinical outcome in breast cancer. PLoS One. 6:e209802011.

24. Rodríguez-González FG, Sieuwerts AM, Smid M, et al: MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat 2011; 127:43–51.

25. Jansen MP, Reijm EA, Sieuwerts AM, et al: High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer. Breast Cancer Res Treat 2012; 133:937–947. 2012.

26. Nguyen, L. V., Vanner, R., Dirks, P., and Eaves, C. J. (2012). Cancer stem cells: an evolving concept. Nat. Rev. Cancer 12, 133–143.

27. Teicher, B. A. (2006). Cancer Drug Resistance. Totowa: Humana Press.

28. Abdullah LN, Chow EK. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2013; 2(1):3.

29. Kelly RJ, Draper D, Chen CC, et al. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res 2011 Feb 1; 17(3):569-80.

30. Rose PG, Mossbruger K, Fusco N, Smrekar M, Eaton S, Rodriguez M. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol 2003; 88(1):17-21.

31. Devchand P, et al "Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy" SABCS 2013; Abstract S3-07.

32. D. B. Longley and P. G. Johnston, “Molecular mechanisms of drug resistance,” Journal of Pathology, vol. 205, no. 2, pp. 275–292, 2005.

33. Yardley DA. Drug resistance and the role of combination chemotherapy in improving patient outcomes. Int J Breast Cancer 2013; 2013:137414.

34. D. B. Longley and P. G. Johnston, “Molecular mechanisms of drug resistance,” Journal of Pathology, vol. 205, no. 2, pp. 275–292, 2005.

35. Smith TE, Lee D, Turner BC, Carter D, Haffty BG. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000 Dec 1; 48(5):1281-9.

36. Nishimura S, Takahashi K, Akiyama F, et al. Classification of ipsilateral breast tumor recurrence after breast-conserving therapy: new primary cancer allows a good prognosis. Breast Cancer 2005; 12(2):112-7.

37. Gujral DM, Sumo G, Owen JR, et al. Ipsilateral breast tumor relapse: local recurrence versus new primary tumor and the effect of whole-breast radiotherapy on the rate of new primaries. Int J Radiat Oncol Biol Phys 2011 Jan 1; 79(1):19-25.

38. Schlechter BL, Yang Q, Larson PS, et al. Quantitative DNA fingerprinting may distinguish new primary breast cancer from disease recurrence. J Clin Oncol 2004 May 15; 22(10):1830-8.

39. Bollet MA, Servant N, Neuvial P, et al. High-resolution mapping of DNA breakpoints to define true recurrences among ipsilateral breast cancers. J Natl Cancer Inst 2008 Jan 2; 100(1):48-58.

40. Abd-Alla HM, Lotayef MM, Abou Bakr A, Moneer MM. Ipsilateral in-breast tumor relapse after breast conservation therapy: true recurrence versus new primary tumor. J Egypt Natl Canc Inst 2006; 18(3):183-90.

41. Yoshida T, Takei H, Kurosumi M, et al. True recurrences and new primary tumors have different clinical features in invasive breast cancer patients with ipsilateral breast tumor relapse after breast-conserving treatment. Breast J 2010 Mar-Apr; 16(2):127-33.

42. West NR, Panet-Raymond V, Truong PT, et al. Intratumoral Immune Responses Can Distinguish New Primary and True Recurrence Types of Ipsilateral Breast Tumor Recurrences (IBTR). Breast Cancer (Auckl) 2011; 5:105-15.

43. Kaniklidis C. A Framework for Trastuzumab Resistance - Translations into the Clinic. [publication pending. Available on ResearchGate profile: https://www.researchgate.net/publication/233860461_A_Framework_for_Trastuzumab_Resistance_-_Translations_into_the_Clinic?ev=prf_pub].

Article A Framework for Trastuzumab Resistance - Translations into the Clinic

What is resistance? Resistance is one of cancer stages. Resistance is multi-factorials. Resistance could occur at local, regional and systemic levels...

Current cancer therapy has not been sufficient to successfully eradicate tumour cells. Considering that it is now believed that many cancers could be driven by a subpopulation of cells with capacity to sustain tumour growth, the CSCs, a CSC-targeted therapy seems to be the best option to totally eradicate the tumour.

Although the mechanisms underlying this resistance are not fully understood, relative dormancy/slow cell cycle kinetics, efficient DNA repair, high expression of multidrug-resistance membrane transporters and resistance to apoptosis seem to be the mechanisms involved in CSC resistance to therapy.

I fully share your views Daniela!

Here attached are some interesting articles.

And the tumor microenvironment is more and more evidenced as a key player in cancer chemoresistance.

The newly marketed natural-derived drug trabectedin targets some of these important features of cancer chemoresistance.

And as you said Daniela, on the "top" of that, metastasis dormancy ...

All the attached articles are going 100% in line with the response of Khalid. And also of Amit!

Best regards

Robert

Here you go!

http://cancerci.biomedcentral.com/articles/10.1186/s12935-015-0221-1

Dear Khalid,

I red with great interest your article and I really appreciate its very clear presentation and the very good highlight on ADME, in addition to the other factor.

I will cite your article in a review that I am currently writing on a group of marine organisms as potential providers of anticancer compound.

Thanks a lot!

Robert