Molecular and Pharmacological Mechanisms of Drug Resistance:An Evolving Paradigm

  • Benedetta Colmegna
  • Lavinia Morosi
  • Maurizio D’IncalciEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


The high heterogeneity and genomic instability of malignant tumors explains why even responsive tumors contain cell clones that are resistant for many possible mechanisms involving intracellular drug inactivation, low uptake or high efflux of anticancer drugs from cancer cells, qualitative or quantitative changes in the drug target. Many tumors, however, are resistant because of insufficient exposure to anticancer drugs, due to pharmacokinetic reasons and inefficient and heterogeneous tumor drug distribution, related to a deficient vascularization and high interstitial pressure. Finally, resistance can be related to the activation of anti-apoptotic and cell survival pathways by cancer cells and often enhanced by tumor microenvironment.


Apoptosis Drug distribution Mass spectrometry imaging Multidrug resistance Pharmacokinetics 


  1. Amable L (2016) Cisplatin resistance and opportunities for precision medicine. Pharmacol Res 106:27–36. doi: 10.1016/j.phrs.2016.01.001 CrossRefPubMedGoogle Scholar
  2. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485. doi: 10.1038/sj.onc.1206948 CrossRefPubMedGoogle Scholar
  3. Ashworth A (2008) Drug resistance caused by reversion mutation. Cancer Res 68:10021–10023. doi: 10.1158/0008-5472.CAN-08-2287 CrossRefPubMedGoogle Scholar
  4. Avery-Kiejda KA, Bowden NA, Croft AJ et al (2011) P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation. BMC Cancer 11:203. doi: 10.1186/1471-2407-11-203 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baekelandt MM, Holm R, Nesland JM et al (2000) P-glycoprotein expression is a marker for chemotherapy resistance and prognosis in advanced ovarian cancer. Anticancer Res 20:1061–1067PubMedGoogle Scholar
  6. Bai L, Zhu WG (2006) p53: structure, function and therapeutic applications. J Cancer Mol 2:141–153Google Scholar
  7. Bell DW, Gore I, Okimoto RA et al (2005) Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 37:1315–1316. doi: 10.1038/ng1671 CrossRefPubMedGoogle Scholar
  8. Buck A, Halbritter S, Späth C et al (2015) Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI. Anal Bioanal Chem 407:2107–2116. doi: 10.1007/s00216-014-8237-2 CrossRefPubMedGoogle Scholar
  9. Cesca M, Morosi L, Berndt A et al (2016) Bevacizumab-induced inhibition of angiogenesis promotes a more homogeneous intratumoral distribution of paclitaxel, improving the antitumor response. Mol Cancer Ther 15:125–135. doi: 10.1158/1535-7163.MCT-15-0063 CrossRefPubMedGoogle Scholar
  10. Chen Z, Naito M, Hori S et al (1999) A human IAP-family gene, apollon, expressed in human brain cancer cells. Biochem Biophys Res Commun 264:847–854. doi: 10.1006/bbrc.1999.1585 CrossRefPubMedGoogle Scholar
  11. Choi YL, Soda M, Yamashita Y et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739. doi: 10.1056/NEJMoa1007478 CrossRefPubMedGoogle Scholar
  12. Connell JJ, Sugihara Y, Török S et al (2015) Localization of sunitinib in in vivo animal and in vitro experimental models by MALDI mass spectrometry imaging. Anal Bioanal Chem 407:2245–2253. doi: 10.1007/s00216-014-8350-2 CrossRefPubMedGoogle Scholar
  13. Croce CM, Reed JC (2016) Finally, an apoptosis-targeting therapeutic for cancer. Cancer Res 76:5914–5920. doi: 10.1158/0008-5472.CAN-16-1248 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Di Nicolantonio F, Mercer SJ, Knight LA et al (2005) Cancer cell adaptation to chemotherapy. BMC Cancer 5:78. doi: 10.1186/1471-2407-5-78 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921. doi: 10.1038/nature03445 CrossRefPubMedGoogle Scholar
  16. Fink D, Aebi S, Howell SB (1998) The role of DNA mismatch repair in drug resistance. Clin Cancer Res 4:1–6PubMedGoogle Scholar
  17. Fuso Nerini I, Morosi L, Zucchetti M et al (2014) Intratumor heterogeneity and its impact on drug distribution and sensitivity. Clin Pharmacol Ther 96:224–238. doi: 10.1038/clpt.2014.105 CrossRefPubMedGoogle Scholar
  18. Garraway LA, Jänne PA (2012) Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2:214–226. doi: 10.1158/2159-8290.CD-12-0012 CrossRefPubMedGoogle Scholar
  19. Giordano S, Morosi L, Veglianese P et al (2016a) 3D mass spectrometry imaging reveals a very heterogeneous drug distribution in tumors. Sci Rep 6:37027. doi: 10.1038/srep37027 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Giordano S, Zucchetti M, Decio A et al (2016b) Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging. Sci Rep 6:39284. doi: 10.1038/srep39284 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gorre ME, Mohammed M, Ellwood K et al (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880. doi: 10.1126/science.1062538 CrossRefPubMedGoogle Scholar
  22. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726. doi: 10.1038/nrc3599 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kao CH, Tsai SC, Liu TJ et al (2001) P-glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings. Cancer Res 61:1412–1414PubMedGoogle Scholar
  24. Kauvar LM, Morgan AS, Sanderson PE, Henner WD (1998) Glutathione based approaches to improving cancer treatment. Chem Biol Interact 111–112:225–238CrossRefGoogle Scholar
  25. Kirschner K, Melton DW (2010) Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res 30:3223–3232PubMedGoogle Scholar
  26. Leith CP, Kopecky KJ, Chen IM et al (1999) Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a southwest oncology group study. Blood 94:1086–1099PubMedGoogle Scholar
  27. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338. doi: 10.1038/nrc1074 CrossRefGoogle Scholar
  28. Meijer C, Mulder NH, Timmer-Bosscha H et al (1992) Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res 52:6885–6889PubMedGoogle Scholar
  29. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583–592. doi: 10.1038/nrc1893 CrossRefPubMedGoogle Scholar
  30. Morosi L, Zucchetti M, D’Incalci M, Davoli E (2013) Imaging mass spectrometry: challenges in visualization of drug distribution in solid tumors. Curr Opin Pharmacol 13:807–812. doi: 10.1016/j.coph.2013.06.003 CrossRefPubMedGoogle Scholar
  31. Pallis M, Russell N (2004) Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia. Leukemia 18:1927–1930. doi: 10.1038/sj.leu.2403511 CrossRefPubMedGoogle Scholar
  32. Poulikakos PI, Persaud Y, Janakiraman M et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390. doi: 10.1038/nature10662 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Prideaux B, Stoeckli M (2012) Mass spectrometry imaging for drug distribution studies. J Proteome 75:4999–5013. doi: 10.1016/j.jprot.2012.07.028 CrossRefGoogle Scholar
  34. Rzagalinski I, Volmer DA (2016) Quantification of low molecular weight compounds by MALDI imaging mass spectrometry – a tutorial review. Biochim Biophys Acta. doi: 10.1016/j.bbapap.2016.12.011. pii:S1570-9639(16)30276-X [Epub ahead of print]CrossRefGoogle Scholar
  35. Shervington A, Lu C (2008) Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Investig 26:535–542. doi: 10.1080/07357900801904140 CrossRefGoogle Scholar
  36. Sugiura Y, Setou M (2010) Imaging mass spectrometry for visualization of drug and endogenous metabolite distribution: toward in situ pharmacometabolomes. J Neuroimmune Pharmacol 5:31–43. doi: 10.1007/s11481-009-9162-6 CrossRefPubMedGoogle Scholar
  37. Szakács G, Paterson JK, Ludwig JA et al (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234. doi: 10.1038/nrd1984 CrossRefPubMedGoogle Scholar
  38. Thomas H, Coley HM (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control J Moffitt Cancer Center 10:159–165CrossRefGoogle Scholar
  39. Thomas A, Tanaka M, Trepel J et al (2017) Temozolomide in the era of precision medicine. Cancer Res 77:823–826. doi: 10.1158/0008-5472.CAN-16-2983 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Torok S, Rezeli M, Kelemen O et al (2017) Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis. Inhibitors. Theranostics 7(2):400–412. doi: 10.7150/thno.16767 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Usanova S, Piée-Staffa A, Sied U et al (2010) Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol Cancer 9:248. doi: 10.1186/1476-4598-9-248 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Wong RSY (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res CR 30:87. doi: 10.1186/1756-9966-30-87 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Benedetta Colmegna
    • 1
  • Lavinia Morosi
    • 1
  • Maurizio D’Incalci
    • 1
    Email author
  1. 1.Department of OncologyIRCCS ‘Mario Negri’, Institute for Pharmacological ResearchMilanItaly

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