Skip to main content
SpringerLink
Log in

Pharmacogenetics in lung cancer for the lay doctor

  • Review
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Lung cancer embodies the conundrum of cancer in general: why some patients with apparently similar tumors respond and others progress. In spite of a plethora of knowledge at the investigational level, in daily practice, the physician is still challenged by the lack both of prognostic markers to identify patients with a high risk of relapse and of predictive markers for customizing chemotherapy and targeted therapy. Multiple microarray studies have deciphered the important network of signaling pathways that can lead to the formation of metastasis, and we are not far from being able to predict the risk of metastasis at a particular site (bone, brain or others) according to specific gene profiles. Quantitative PCR has allowed the assessment of mRNA expression levels of key genes, identified mostly by transcriptome analysis. Growing evidence indicates that three-or five-gene signatures by quantitative PCR are highly predictive of metastasis and survival in early-stage non-small cell lung cancer, including stage IB, paving the way for the selection of high-risk patients for adjuvant chemotherapy and for the customization of treatment. A meaningful proportion of lung cancer patients are EGFR-driven, and abundant knowledge has enabled us to identify extensive networks of downstream signals that collapse when drug treatment is effective. Novel mechanisms of resistance to chemotherapy and targeted therapies can be useful for personalizing treatment and can lead to the implementation of novel targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  2. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  3. Pao W, Miller V, Zakowski M, Doherty J, Politi K et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–13311

    Article  PubMed  CAS  Google Scholar 

  4. Taron M, Ichinose Y, Rosell R, Mok T, Massuti B et al (2005) Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 11:5878–5885

    Article  PubMed  CAS  Google Scholar 

  5. Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C et al (2005) Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small cell lung cancer patients. Ann Oncol 16:1081–1086

    Article  PubMed  CAS  Google Scholar 

  6. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  7. Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A et al (2006) A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 355:570–580

    Article  PubMed  CAS  Google Scholar 

  8. Bild AH, Yao G, Chang JT, Wang Q, Potti A et al (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353–357

    Article  PubMed  CAS  Google Scholar 

  9. Potti A, Dressman HK, Bild A, Riedel RF, Chan G et al (2006) Genomic signatures to guide the use of chemotherapeutics. Nat Med 12:1294–1300

    Article  PubMed  CAS  Google Scholar 

  10. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB et al (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2:E7

    Article  PubMed  Google Scholar 

  11. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q et al (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152

    Article  PubMed  CAS  Google Scholar 

  12. Adler AS, Lin M, Horlings H, Nuyten DS, van de Vijver MJ et al (2006) Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38:421–430

    Article  PubMed  CAS  Google Scholar 

  13. Adler AS, Littlepage LE, Lin M, Kawahara TL, Wong DJ et al (2008) CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression. Cancer Res 68:506–515

    Article  PubMed  CAS  Google Scholar 

  14. Bae MK, Ahn MY, Jeong JW, Bae MH, Lee YM et al (2002) Jab1 interacts directly with HIF-1alpha and regulates its stability. J Biol Chem 277:9–12

    Article  PubMed  CAS  Google Scholar 

  15. Lau SK, Boutros PC, Pintilie M, Blackhall FH, Zhu CQ et al (2007) Three-gene prognostic classifier for early-stage non small-cell lung cancer. J Clin Oncol 25:5562–5569

    Article  PubMed  Google Scholar 

  16. Wong DJ, Nuyten DS, Regev A, Lin M, Adler AS et al (2008) Revealing targeted therapy for human cancer by gene module maps. Cancer Res 68:369–378

    Article  PubMed  CAS  Google Scholar 

  17. Lipford JR, Smith GT, Chi Y, Deshaies RJ (2005) A putative stimulatory role for activator turnover in gene expression. Nature 438:113–116

    Article  PubMed  CAS  Google Scholar 

  18. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME et al (2006) Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 3:e47

    Article  PubMed  Google Scholar 

  19. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524

    Article  PubMed  CAS  Google Scholar 

  20. Liu R, Wang X, Chen GY, Dalerba P, Gurney A et al (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356:217–226

    Article  PubMed  CAS  Google Scholar 

  21. Massague J (2007) Sorting out breast-cancer gene signatures. N Engl J Med 356:294–297

    Article  PubMed  CAS  Google Scholar 

  22. Pignon JP, Tribodet H, Scagliotti G, Douillard JY, Shepherd F et al (2008) Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of five randomized trials including 4,584 patients. J Clin Oncol 24:366

    Google Scholar 

  23. Endoh H, Tomida S, Yatabe Y, Konishi H, Osada H et al (2004) Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J Clin Oncol 22:811–819

    Article  PubMed  CAS  Google Scholar 

  24. Chen HY, Yu SL, Chen CH, Chang GC, Chen CY et al (2007) A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 356:11–20

    Article  PubMed  CAS  Google Scholar 

  25. Kobayashi S, Shimamura T, Monti S, Steidl U, Hetherington CJ et al (2006) Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling. Cancer Res 66:11389–11398

    Article  PubMed  CAS  Google Scholar 

  26. Yu SL, Chen HY, Chang GC, Chen CY, Chen HW et al (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57

    Article  PubMed  CAS  Google Scholar 

  27. Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K et al (2007) The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 67:7713–7722

    Article  PubMed  CAS  Google Scholar 

  28. Rosell R, Skrzypski M, Jassem E, Taron M, Bartolucci R et al (2007) BRCA1: a novel prognostic factor in resected non-small cell lung cancer. PLoS ONE 2:e1129

    Article  PubMed  Google Scholar 

  29. Quinn JE, Kennedy RD, Mullan PB, Gilmore PM, Carty M et al (2003) BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res 63:6221–6228

    PubMed  CAS  Google Scholar 

  30. Quinn JE, James CR, Stewart GE, Mulligan JM, White P et al (2007) BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13:7413–7420

    Article  PubMed  CAS  Google Scholar 

  31. Taron M, Rosell R, Felip E, Mendez P, Souglakos J et al (2004) BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum Mol Genet 13:2443–2449

    Article  PubMed  CAS  Google Scholar 

  32. Deeb KK, Michalowska AM, Yoon CY, Krummey SM, Hoenerhoff MJ et al (2007) Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis. Cancer Res 67:8065–8080

    Article  PubMed  CAS  Google Scholar 

  33. Menssen A, Hermeking H (2002) Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A 99:6274–6279

    Article  PubMed  CAS  Google Scholar 

  34. Rosell R, Mendez P, Isla D, Taron M (2007) Platinum resistance related to a functional NER pathway. J Thorac Oncol 2:1063–1066

    Article  PubMed  Google Scholar 

  35. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM et al (2007) Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol 25:2747–2754

    Article  PubMed  CAS  Google Scholar 

  36. Rosell R, Taron M, Santarpia M, Salazar F, Ramirez JL et al (2008) DNA repair and mitotic checkpoint genes as potential predictors of chemotherapy response in non-small cell lung cancer. In: Innocenti F (ed) Pharmacogenomics, anticancer drug discovery, and response. Humana, Totowa, NJ (in press)

    Google Scholar 

  37. Chen CC, Chen LT, Tsou TC, Pan WY, Kuo CC et al (2007) Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil. Br J Cancer 97:334–344

    Article  PubMed  CAS  Google Scholar 

  38. Fan T, Li R, Todd NW, Qiu Q, Fang HB et al (2007) Up-regulation of 14-3-3zeta in lung cancer and its implication as prognostic and therapeutic target. Cancer Res 67:7901–7906

    Article  PubMed  CAS  Google Scholar 

  39. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  PubMed  CAS  Google Scholar 

  40. Lee AS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499

    Article  PubMed  CAS  Google Scholar 

  41. Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163–1167

    Article  PubMed  CAS  Google Scholar 

  42. Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP et al (2008) Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A 105:692–697

    Article  PubMed  CAS  Google Scholar 

  43. Bruce B, Khanna G, Ren L, Landberg G, Jirstrom K et al (2007) Expression of the cytoskeleton linker protein ezrin in human cancers. Clin Exp Metastasis 24:69–78

    Article  PubMed  CAS  Google Scholar 

  44. Deng X, Tannehill-Gregg SH, Nadella MV, He G, Levine A et al (2007) Parathyroid hormone-related protein and ezrin are up-regulated in human lung cancer bone metastases. Clin Exp Metastasis 24:107–119

    Article  PubMed  CAS  Google Scholar 

  45. Janmaat ML, Rodriguez JA, Gallegos-Ruiz M, Kruyt FA, Giaccone G (2006) Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer 118:209–214

    Article  PubMed  CAS  Google Scholar 

  46. Bean J, Brennan C, Shih JY, Riely G, Viale A et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104:20932–20937

    Article  PubMed  CAS  Google Scholar 

  47. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  48. Rosell R, Taron M, Reguart N, Isla D, Moran T (2006) Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clin Cancer Res 12:7222–7231

    Article  PubMed  CAS  Google Scholar 

  49. Yang H, Kong W, He L, Zhao JJ, O’Donnell JD et al (2008) MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68:425–433

    Article  PubMed  CAS  Google Scholar 

  50. Ji H, Li D, Chen L, Shimamura T, Kobayashi S et al (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9:485–495

    Article  PubMed  CAS  Google Scholar 

  51. Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W et al (2006) Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20:1496–1510

    Article  PubMed  CAS  Google Scholar 

  52. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS et al (2007) BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4:1669–1679 discussion 1680

    Article  PubMed  CAS  Google Scholar 

  53. Gong Y, Somwar R, Politi K, Balak M, Chmielecki J et al (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4:e294

    Article  PubMed  Google Scholar 

  54. Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A (2007) Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4:1681–1689 discussion 1690

    Article  PubMed  CAS  Google Scholar 

  55. Deng J, Shimamura T, Perera S, Carlson NE, Cai D et al (2007) Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res 67:11867–11875

    Article  PubMed  CAS  Google Scholar 

  56. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD et al (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117:112–121

    Article  PubMed  CAS  Google Scholar 

  57. de La Motte Rouge T, Galluzzi L, Olaussen KA, Zermati Y, Tasdemir E et al (2007) A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res 67:6253–6262

    Article  PubMed  Google Scholar 

  58. Rosell R, Taron M, Sanchez JJ, Paz-Ares L (2007) Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol 3:277–283

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work summarizes the discussions held during a workshop organized jointly by the Spanish Lung Cancer Group and the Groupe Français de Pneumo-Cancérologie in January 2008.

Conflict of interest statement

No funds were received to support this study.

Author information

Authors and Affiliations

  1. Catalan Institute of Oncology, Badalona, Spain

    Rafael Rosell, Teresa Moran & Miquel Taron

  2. USP Institut Universitari Dexeus, Barcelona, Spain

    Rafael Rosell & Miquel Taron

  3. CHU Limoges, Limoges, France

    Alain Vergnenegre

  4. Institut de Cancérologie, St Priest en Jarez, France

    Pierre Fournel

  5. Hospital General de Alicante, Alicante, Spain

    Bartomeu Massuti

  6. Hospital General de Valencia, Valencia, Spain

    Carlos Camps & Rafael Sirera

  7. Hospital Lozano Blesa, Zaragoza, Spain

    Dolores Isla

  8. Hospital 12 de Octubre, Madrid, Spain

    Jose Miguel Sanchez

  9. Medical Oncology Service, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916, Badalona, Barcelona, Spain

    Rafael Rosell

Authors
  1. Rafael Rosell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alain Vergnenegre
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Fournel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bartomeu Massuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlos Camps
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dolores Isla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jose Miguel Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Teresa Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rafael Sirera
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Miquel Taron
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Rosell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosell, R., Vergnenegre, A., Fournel, P. et al. Pharmacogenetics in lung cancer for the lay doctor. Targ Oncol 3, 161–171 (2008). https://doi.org/10.1007/s11523-008-0083-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-008-0083-8

Keywords

Search

Navigation