Skip to main content
SpringerLink
Log in

A Personalized Treatment for Lung Cancer: Molecular Pathways, Targeted Therapies, and Genomic Characterization

  • Chapter
  • First Online:
Systems Analysis of Human Multigene Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 799))

Abstract

Lung cancer is a heterogeneous, complex, and challenging disease to treat. With the arrival of genotyping and genomic profiling, our simple binary division of lung cancer into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) is no longer acceptable. In the past decade and with the advent of personalized medicine, multiple advances have been made in understanding the underlying biology and molecular mechanisms of lung cancer. Lung cancer is no longer considered a single disease entity and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient’s tumor to make therapeutic and treatment decisions has revolutionized the landscape for cancer care and research in general.

Management of non-small-cell lung cancer, in particular, has seen several of these advances, with the understanding of activating mutations in EGFR, fusion genes involving ALK, rearrangements in ROS-1, and ongoing research in targeted therapies for K-RAS and MET. The next era of personalized treatment for lung cancer will involve a comprehensive genomic characterization of adenocarcinoma, squamous-cell carcinoma, and small-cell carcinoma into various subtypes. Future directions will involve incorporation of molecular characteristics and next generation sequencing into screening strategies to improve early detection, while also having applications for joint treatment decision making in the clinics with patients and practitioners. Personalization of therapy will involve close collaboration between the laboratory and the clinic. Given the heterogeneity and complexity of lung cancer treatment with respect to histology, tumor stage, and genomic characterization, mind mapping has been developed as one of many tools which can assist physicians in this era of personalized medicine. We attempt to utilize the above tool throughout this chapter, while reviewing lung cancer epidemiology, lung cancer treatment, and the genomic characterization of lung cancer.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ALK:

Anaplastic lymphoma kinase

ASCO:

American Society of Clinical Oncology

CI:

Confidence interval

c-MET:

N-methyl-N’-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene

CT:

Computed tomography

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EML4:

Echinoderm microtubule-associated protein-like 4

EMT:

Epithelial to mesenchymal transition

ERCC1:

Excision repair cross-complementation group 1

EZH2:

Enhancer of zeste homolog 2

FDA:

Food and Drug Administration

FISH:

Fluorescence in situ hybridization

GDP:

Guanosine diphosphate

GTP:

Guanosine triphosphate

HDAC:

Histone deacetylase

HGF/SF:

Hepatocyte growth factor/scatter factor

HGFR:

Hepatocyte growth factor receptor

HR:

Hazard ratio

HSP-90:

Heat shock protein-90

IGFR1:

Insulin-like growth factor receptor 1

IHC:

Immunohistochemistry

IPASS:

Iressa Pan-Asia Study

LDCT:

Low-dose computed tomography

MEK:

Mitogen-activated protein kinase kinase

MTD:

Maximum tolerated dose

mTOR:

Mammalian target of rapamycin

NCCN:

National Comprehensive Cancer Network

NGS:

Next generation sequencing

NSCLC:

Non-small-cell lung cancer

OR:

Odds ratio

OS:

Overall survival

PCR:

Polymerase chain reaction

PET:

Positron emission tomography

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol 3-kinase

ROS-1:

Reactive oxygen species-1

RT:

Radiation therapy

RTK:

Receptor tyrosine kinase

RTOG:

Radiation Therapy Oncology Group

SCLC:

Small-cell lung cancer

Siah 2:

Seven in absentia homolog 2

TKI:

Tyrosine kinase inhibitor

TP63:

Tumor protein 63

TS:

Thymidylate synthase

TTF-1:

Thyroid transcription factor

VATS:

Video-assisted thoracoscopic surgery

VEGF:

Vascular endothelial growth factor

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    PubMed  Google Scholar 

  2. Malvezzi M, Bertuccio P, Levi F et al (2013) European cancer mortality predictions for the year 2013. Ann Oncol 24(3):792–800

    PubMed  CAS  Google Scholar 

  3. American Cancer Society (2012) Cancer facts & figures. Atlanta, American Cancer Society

    Google Scholar 

  4. Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review (1975–2007) National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/975_2007/based on Nov 2009 SEER data submission, posted to the SEER website, 2010. Accessed 24 Feb 2013

  5. Health Service, Centers for Disease Control and Prevention, Washington, DC, 2010. Smoking and tobacco use – fact sheets. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/. Accessed 24 Feb 2013

  6. Schroeder SA (2013) New evidence that cigarette smoking remains the most important health hazard. N Engl J Med 368(4):389–390

    PubMed  CAS  Google Scholar 

  7. Alberg AJ, Nonemaker J (2008) Who is at high risk for lung cancer? Population-level and individual-level perspectives. Semin Respir Crit Care Med 29(3):223–232

    PubMed  Google Scholar 

  8. Godtfredsen NS, Prescott E, Osler M (2005) Effect of smoking reduction on lung cancer risk. JAMA 294(12):1505–1510

    PubMed  CAS  Google Scholar 

  9. Bruske-Hohlfeld I (2009) Environmental and occupational risk factors for lung cancer. Methods Mol Biol 472:3–23

    PubMed  Google Scholar 

  10. Sim MR (2013) A worldwide ban on asbestos production and use: some recent progress, but more still to be done. Occup Environ Med 70(1):1–2

    PubMed  Google Scholar 

  11. Matakidou A, Eisen T, Houlston RS (2005) Systematic review of the relationship between family history and lung cancer risk. Br J Cancer 93(7):825–833

    PubMed  CAS  Google Scholar 

  12. Ihsan R, Chauhan PS, Mishra AK et al (2011) Multiple analytical approaches reveal distinct gene-environment interactions in smokers and non smokers in lung cancer. PLoS One 6(12):e29431

    PubMed  CAS  Google Scholar 

  13. Tockman MS (1986) Survival and mortality from lung cancer in a screened population. Chest 89(4 suppl):324S–325S

    Google Scholar 

  14. Tockman MS, Mulshine JL (1997) Sputum screening by quantitative microscopy: a new dawn for detection of lung cancer? Mayo Clin Proc 72(8):788–790

    PubMed  CAS  Google Scholar 

  15. Prorok PC, Andriole GL, Bresalier RS et al (2000) Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control Clin Trials 21(6 Suppl):273S–309S

    PubMed  CAS  Google Scholar 

  16. Bach PB, Mirkin JN, Oliver TK et al (2012) Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307(22):2418–2429

    PubMed  CAS  Google Scholar 

  17. Aberle DR, Adams AM, Berg CD, et al, for the National Lung Screening Trial Research Team (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365(5):395–409

    Google Scholar 

  18. Dancey JE, Dobbin KK, Groshen S et al (2010) Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res 16(6):1745–1755

    PubMed  CAS  Google Scholar 

  19. Johnson DH, Fehrenbacher L, Novotny WF et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22(11):2184–2191

    PubMed  CAS  Google Scholar 

  20. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    PubMed  CAS  Google Scholar 

  21. Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551

    PubMed  CAS  Google Scholar 

  22. Ciuleanu T, Brodowicz T, Zielinski C et al (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440

    PubMed  CAS  Google Scholar 

  23. Giovannetti E, Mey V, Nannizzi S et al (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68(1):110–118

    PubMed  CAS  Google Scholar 

  24. Maziak DE, Darling GE, Inculet RI et al (2009) Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med 151(4):221–228, W-48

    PubMed  Google Scholar 

  25. Luke WP, Pearson FG, Todd TR et al (1986) Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung. J Thorac Cardiovasc Surg 91(1):53–56

    PubMed  CAS  Google Scholar 

  26. Vilmann P, Krasnik M, Larsen SS et al (2005) Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy 37(9):833–839

    PubMed  CAS  Google Scholar 

  27. Goldstraw P (2009) The 7th edition of TNM in lung cancer: what now? J Thorac Oncol 4(6):671–673

    PubMed  Google Scholar 

  28. Groome PA, Bolejack V, Crowley JJ et al (2007) The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2(8):694–705

    PubMed  Google Scholar 

  29. Doddoli C, D'Journo B, Le Pimpec-Barthes F et al (2005) Lung cancer invading the chest wall: a plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80(6):2032–2040

    PubMed  Google Scholar 

  30. Yan TD, Black D, Bannon PG et al (2009) Systematic review and meta-analysis of randomized and nonrandomized trials on safety and efficacy of video-assisted thoracic surgery lobectomy for early-stage non-small-cell lung cancer. J Clin Oncol 27(15):2553–2562

    PubMed  Google Scholar 

  31. Petersen RP, Pham D, Burfeind WR et al (2007) Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg 83(4):1245–1249, discussion 50

    PubMed  Google Scholar 

  32. Ferguson MK, Lehman AG (2003) Sleeve lobectomy or pneumonectomy: optimal management strategy using decision analysis techniques. Ann Thorac Surg 76(6):1782–1788

    PubMed  Google Scholar 

  33. Strauss GM, Herndon JE 2nd, Maddaus MA et al (2008) Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26(31):5043–5051

    PubMed  CAS  Google Scholar 

  34. Heon S, Johnson BE (2012) Adjuvant chemotherapy for surgically resected non-small cell lung cancer. J Thorac Cardiovasc Surg 144(3):S39–S42

    PubMed  CAS  Google Scholar 

  35. Douillard JY, Rosell R, De Lena M et al (2006) Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7(9):719–727

    PubMed  CAS  Google Scholar 

  36. Pisters KM, Evans WK, Azzoli CG et al (2007) Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 25(34):5506–5518

    PubMed  Google Scholar 

  37. Douillard JY, Rosell R, De Lena M et al (2008) Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 72(3):695–701

    PubMed  CAS  Google Scholar 

  38. Curran WJ Jr, Paulus R, Langer CJ et al (2011) Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103(19):1452–1460

    PubMed  CAS  Google Scholar 

  39. Pao W, Hutchinson KE (2012) Chipping away at the lung cancer genome. Nat Med 18(3):349–351

    PubMed  CAS  Google Scholar 

  40. Kris MG, Johnson BE, Kwiatkowski DJ et al (2011) Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 29:477s, suppl 15; abstr CRA 7506

    Google Scholar 

  41. Vignot S, Frampton GM, Soria JC et al (2013). Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. Epub ahead of print.

    Google Scholar 

  42. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13):1367–1380

    PubMed  CAS  Google Scholar 

  43. Herbst RS, Maddox AM, Rothenberg ML et al (2002) Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 20(18):3815–3825

    PubMed  CAS  Google Scholar 

  44. Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21(12):2237–2246

    PubMed  CAS  Google Scholar 

  45. Lynch TJ, Bell DW, Sordella R 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(21):2129–2139

    PubMed  CAS  Google Scholar 

  46. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500

    PubMed  CAS  Google Scholar 

  47. Marks JL, Broderick S, Zhou Q et al (2008) Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 3(2):111–116

    PubMed  Google Scholar 

  48. Pao W, Chmielecki J (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10(11):760–774

    PubMed  CAS  Google Scholar 

  49. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957

    PubMed  CAS  Google Scholar 

  50. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388

    PubMed  CAS  Google Scholar 

  51. Mitsudomi T, Morita S, Yatabe Y et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11(2):121–128

    PubMed  CAS  Google Scholar 

  52. Rosell R, Moran T, Queralt C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967

    PubMed  CAS  Google Scholar 

  53. Sequist LV, Waltman BA, Dias-Santagata D et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3(75):75ra26

    PubMed  Google Scholar 

  54. Soh J, Okumura N, Lockwood WW et al (2009) Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One 4(10):e7464

    PubMed  Google Scholar 

  55. Ding L, Getz G, Wheeler DA et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075

    PubMed  CAS  Google Scholar 

  56. Yun CH, Boggon TJ, Li Y et al (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3):217–227

    PubMed  CAS  Google Scholar 

  57. Carey KD, Garton AJ, Romero MS et al (2006) Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res 66(16):8163–8171

    PubMed  CAS  Google Scholar 

  58. Gong Y, Somwar R, Politi K et al (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4(10):e294

    PubMed  Google Scholar 

  59. Deng J, Shimamura T, Perera S 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(24):11867–11875

    PubMed  CAS  Google Scholar 

  60. Greulich H, Chen TH, Feng W et al (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2(11):e313

    PubMed  Google Scholar 

  61. Prudkin L, Tang X, Wistuba II (2009) Germ-line and somatic presentations of the EGFR T790M mutation in lung cancer. J Thorac Oncol 4(1):139–141

    PubMed  Google Scholar 

  62. Pao W, Wang TY, Riely GJ et al (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2(1):e17

    PubMed  Google Scholar 

  63. Roberts PJ, Stinchcombe TE (2013) KRAS mutation: should we test for it, and does it matter? J Clin Oncol 31(8):1112–1121

    PubMed  CAS  Google Scholar 

  64. Sos ML, Koker M, Weir BA et al (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69(8):3256–3261

    PubMed  CAS  Google Scholar 

  65. Yano S, Wang W, Li Q et al (2008) Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 68(22):9479–9487

    PubMed  CAS  Google Scholar 

  66. Jackman D, Pao W, Riely GJ et al (2010) Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 28(2):357–360

    PubMed  CAS  Google Scholar 

  67. Yun CH, Mengwasser KE, Toms AV et al (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 105(6):2070–2075

    PubMed  CAS  Google Scholar 

  68. Oxnard GR, Arcila ME, Sima CS et al (2011) Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 17(6):1616–1622

    PubMed  CAS  Google Scholar 

  69. Bean J, Riely GJ, Balak M et al (2008) Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 14(22):7519–7525

    PubMed  CAS  Google Scholar 

  70. Bean J, Brennan C, Shih JY 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(52):20932–20937

    PubMed  CAS  Google Scholar 

  71. Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827):1039–1043

    PubMed  CAS  Google Scholar 

  72. Wilson TR, Fridlyand J, Yan Y et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487(7408):505–509

    PubMed  CAS  Google Scholar 

  73. Jagadeeswaran R, Surawska H, Krishnaswamy S et al (2008) Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. Cancer Res 68(1):132–142

    PubMed  CAS  Google Scholar 

  74. Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504

    PubMed  CAS  Google Scholar 

  75. Li D, Ambrogio L, Shimamura T et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34):4702–4711

    PubMed  CAS  Google Scholar 

  76. Xu L, Kikuchi E, Xu C et al (2012) Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res 72(13):3302–3311

    PubMed  CAS  Google Scholar 

  77. Yang JC-H, Schuler MH, Yamamoto N et al LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. 2012 ASCO annual meeting. Abstract LBA7500. Presented 4 June 2012.

    Google Scholar 

  78. Li D, Shimamura T, Ji H et al (2007) Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12(1):81–93

    PubMed  CAS  Google Scholar 

  79. Chaft JE, Oxnard GR, Sima CS et al (2011) Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 17(19):6298–6303

    PubMed  CAS  Google Scholar 

  80. Turke AB, Zejnullahu K, Wu YL et al (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17(1):77–88

    PubMed  CAS  Google Scholar 

  81. Morris SW, Kirstein MN, Valentine MB et al (1995) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 267(5196):316–317

    PubMed  CAS  Google Scholar 

  82. Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566

    PubMed  CAS  Google Scholar 

  83. Horn L, Pao W (2009) EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27(26):4232–4235

    PubMed  CAS  Google Scholar 

  84. Shaw AT, Yeap BY, Mino-Kenudson M et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27(26):4247–4253

    PubMed  CAS  Google Scholar 

  85. Koivunen JP, Mermel C, Zejnullahu K et al (2008) EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 14(13):4275–4283

    PubMed  CAS  Google Scholar 

  86. Camidge DR, Bang Y, Kwak EL et al (2011) Progression-free survival (PFS) from a phase 1 study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 29(15 suppl):2501

    Google Scholar 

  87. 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(18):1734–1739

    PubMed  CAS  Google Scholar 

  88. Rikova K, Guo A, Zeng Q et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203

    PubMed  CAS  Google Scholar 

  89. Bergethon K, Shaw AT, Ou SH et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870

    PubMed  CAS  Google Scholar 

  90. McDermott U, Iafrate AJ, Gray NS et al (2008) Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68(9):3389–3395

    PubMed  CAS  Google Scholar 

  91. Mascaux C, Iannino N, Martin B et al (2005) The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 92(1):131–139

    PubMed  CAS  Google Scholar 

  92. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22):3291–3310

    PubMed  CAS  Google Scholar 

  93. Slebos RJ, Kibbelaar RE, Dalesio O et al (1990) K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323(9):561–565

    PubMed  CAS  Google Scholar 

  94. Riely GJ, Kris MG, Rosenbaum D et al (2008) Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 14(18):5731–5734

    PubMed  CAS  Google Scholar 

  95. Graziano SL, Gamble GP, Newman NB et al (1999) Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 17(2):668–675

    PubMed  CAS  Google Scholar 

  96. Mao C, Qiu LX, Liao RY et al (2010) KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 69(3):272–278

    PubMed  Google Scholar 

  97. Linardou H, Dahabreh IJ, Kanaloupiti D et al (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9(10):962–972

    PubMed  CAS  Google Scholar 

  98. Chen Z, Cheng K, Walton Z et al (2012) A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483(7391):613–617

    PubMed  CAS  Google Scholar 

  99. Engelman JA, Chen L, Tan X et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14(12):1351–1356

    PubMed  CAS  Google Scholar 

  100. Sos ML, Michel K, Zander T et al (2009) Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. J Clin Invest 119(6):1727–1740

    PubMed  CAS  Google Scholar 

  101. Corcoran RB, Cheng KA, Hata AN et al (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23(1):121–128

    PubMed  CAS  Google Scholar 

  102. Puyol M, Martin A, Dubus P et al (2010) A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18(1):63–73

    PubMed  CAS  Google Scholar 

  103. Vicent S, Chen R, Sayles LC et al (2010) Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. J Clin Invest 120(11):3940–3952

    PubMed  CAS  Google Scholar 

  104. Meylan E, Dooley AL, Feldser DM et al (2009) Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 462(7269):104–107

    PubMed  CAS  Google Scholar 

  105. Barbie DA, Tamayo P, Boehm JS et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108–112

    PubMed  CAS  Google Scholar 

  106. Huqun, Ishikawa R, Zhang J et al (2012) Enhancer of zeste homolog 2 is a novel prognostic biomarker in nonsmall cell lung cancer. Cancer 118(6):1599–1606

    PubMed  CAS  Google Scholar 

  107. Ahmed AU, Schmidt RL, Park CH et al (2008) Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. J Natl Cancer Inst 100(22):1606–1629

    PubMed  CAS  Google Scholar 

  108. Kumar MS, Hancock DC, Molina-Arcas M et al (2012) The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149(3):642–655

    PubMed  CAS  Google Scholar 

  109. Sunaga N, Imai H, Shimizu K et al (2012) Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer. Int J Cancer 130(8):1733–1744

    PubMed  CAS  Google Scholar 

  110. Seo JS, Ju YS, Lee WC et al (2012) The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22(11):2109–2119

    PubMed  CAS  Google Scholar 

  111. Ma PC, Jagadeeswaran R, Jagadeesh S et al (2005) Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 65(4):1479–1488

    PubMed  CAS  Google Scholar 

  112. Cappuzzo F, Marchetti A, Skokan M et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27(10):1667–1674

    PubMed  Google Scholar 

  113. Peruzzi B, Bottaro DP (2006) Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 12(12):3657–3660

    PubMed  CAS  Google Scholar 

  114. Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925

    PubMed  CAS  Google Scholar 

  115. Sulpice E, Ding S, Muscatelli-Groux B et al (2009) Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells. Biol Cell (Under the auspices of the European Cell Biology Organization) 101(9):525–539

    CAS  Google Scholar 

  116. Spigel DR, Ervin TJ, Ramlau R et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol 29: 2011 (suppl; abstr 7505)

    Google Scholar 

  117. Schiller JH, Akerley WL, Brugger W et al (2010) Results from ARQ 197–209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28:18s (suppl; abstr LBA7502)

    Google Scholar 

  118. Burke A. Foundation medicine: personalizing cancer drugs. MIT Technol Rev. http://www.technologyreview.com/. Accessed 21 Feb 2012

  119. Heger M. Caris Adds Next-Gen Sequencing to portfolio of molecular tumor profiling technologies. Clinical sequencing news. http://www.genomeweb.com/. Accessed 06 Feb 2013

  120. Roth JA, Carlson JJ (2011) Prognostic role of ERCC1 in advanced non-small-cell lung cancer: a systematic review and meta-analysis. Clin Lung Cancer 12(6):393–401

    PubMed  CAS  Google Scholar 

  121. Reynolds C, Obasaju C, Schell MJ et al (2009) Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol 27(34):5808–5815

    PubMed  CAS  Google Scholar 

  122. Friboulet L, Olaussen KA, Pignon JP et al (2013) ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med 368(12):1101–1110

    PubMed  CAS  Google Scholar 

  123. Li T, Kung HJ, Mack PC et al (2013) Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 31(8):1039–1049

    PubMed  CAS  Google Scholar 

  124. Thomas RK, Baker AC, Debiasi RM et al (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39(3):347–351

    PubMed  CAS  Google Scholar 

  125. Su Z, Dias-Santagata D, Duke M et al (2011) A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J Mol Diagn 13(1):74–84

    PubMed  CAS  Google Scholar 

  126. Sequist LV, Heist RS, Shaw AT et al (2011) Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 22(12):2616–2624

    PubMed  CAS  Google Scholar 

  127. Govindan R, Ding L, Griffith M et al (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150(6):1121–1134

    PubMed  CAS  Google Scholar 

  128. Imielinski M, Berger AH, Hammerman PS et al (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150(6):1107–1120

    PubMed  CAS  Google Scholar 

  129. Peifer M, Fernandez-Cuesta L, Sos ML et al (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44(10):1104–1110

    PubMed  CAS  Google Scholar 

  130. Rudin CM, Durinck S, Stawiski EW et al (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44(10): 1111–1116

    PubMed  CAS  Google Scholar 

  131. Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489(7417):519–525

    Google Scholar 

  132. Arcila ME, Oxnard GR, Nafa K et al (2011) Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 17(5):1169–1180

    PubMed  CAS  Google Scholar 

  133. Oxnard GR, Arcila ME, Chmielecki J et al (2011) New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res 17(17):5530–5537

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, NorthShore University Health System, Kellogg Cancer Center, 2650 Ridge Avenue, Evanston, IL, 60201, USA

    Thomas Hensing M.D.

  2. Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, USA

    Thomas Hensing M.D., Apoorva Chawla M.D. & Ravi Salgia M.D., Ph.D.

  3. 987400 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Rishi Batra B.S.

Authors
  1. Thomas Hensing M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Apoorva Chawla M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rishi Batra B.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ravi Salgia M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Hensing M.D. .

Editor information

Editors and Affiliations

  1. University of Chicago, Chicago, Illinois, USA

    Natalia Maltsev

  2. University of Chicago, Chicago, Illinois, USA

    Andrey Rzhetsky

  3. University of Chicago, Chicago, Illinois, USA

    T. Conrad Gilliam

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hensing, T., Chawla, A., Batra, R., Salgia, R. (2014). A Personalized Treatment for Lung Cancer: Molecular Pathways, Targeted Therapies, and Genomic Characterization. In: Maltsev, N., Rzhetsky, A., Gilliam, T. (eds) Systems Analysis of Human Multigene Disorders. Advances in Experimental Medicine and Biology, vol 799. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8778-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation