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Lung Cancer Receptors and Targeting Strategies

  • Uday Koli
  • Anomitra Dey
  • P. Nagendra
  • Padma V. Devarajan
  • Ratnesh JainEmail author
  • Prajakta DandekarEmail author
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 39)

Abstract

Lung cancer still remains the leading cause of cancer-related deaths worldwide. Till now, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) have effectively responded to conventional therapy. However, because of cancer nature and subsequent side effects of conventional therapy, inventing novel drug targets for lung cancer therapies has become essential. The disease management recently has seen a paradigm shift with the advent of next-generation sequencing, which has extensively affected the disease prognosis and hence led to newer targeted therapies. Receptors particularly have played an important role as molecular targets and hence presented new opportunities for intracellular targeting of drug delivery systems. Such approach for therapy not only improves the efficacy of the drug but also reduces the overall systemic cytotoxicity. This chapter extensively focuses on such receptors targeted for lung cancer therapy. Further, the role of receptors like epidermal growth factor receptor (EGFR), c-MET, and vascular endothelial growth factor (VEGF) has been discussed with respect to their appropriate ligand(s) binding and developed nanocarrier system for targeting. In addition, this chapter presents the current status of clinical outcomes of conventional drugs in targeting these receptors and thus improving the overall survival rate in patients suffering from this dreaded disease.

Keywords

Lung cancer epidermal growth factor receptor (EGFR) ligand targeting c-MET receptor vascular endothelial growth factor receptor 

Abbreviations

ADC

Adenocarcinomas

ALK

Anaplastic lymphoma kinase

AREG

Amphiregulin

ADCC

Antibody-mediated cellular cytotoxicity

ATP

Adenosine triphosphate

ADAM

A disintegrin and metalloproteinase

BTC

Betacellulin

CRR

Confirmed response rate

EGF

Epidermal growth factor

EPG

Epigen

EPR

Epiregulin

EGFR

Epidermal growth factor receptor

Grb2

Growth factor receptor-bound protein 2

HAP

Hypoxia-activated prodrugs

HIF-1α

Hypoxia inducible factor-1α

HGF

Hepatocyte growth factor

HGFR

Hepatocyte growth factor receptor

HB-EGF

Heparin-binding EGF

mAbs

Monoclonal antibodies

MAPK

Mitogen-activated protein kinase

NSCLC

Non-small cell lung cancer

NRG

Neuregulins

ORR

Objective response rate

PI3K

Phosphatidylinositol 3′-kinase

PLC

Phospholipase C

PLC-γ

Phospholipase C-γ

PEI

Polyethylenimine

RTKs

Receptor tyrosine kinases

SCC

Squamous cell carcinomas

SCLC

Small cell lung cancer

STATs

Signal transducers and activators of transcription

SAR

Structure activity relationship

ScFv

Single chain variable fragment

TGF-α

Transforming growth factor alpha

TKIs

Tyrosine kinase inhibitors

TGFβ1

Transforming growth factor beta 1

TNFα

Tumor necrosis factor alpha

VEGF

Vascular endothelial growth factor

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.  https://doi.org/10.3322/caac.21442.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    O’Brien TD, Jia P, Aldrich MC, Zhao Z. Lung cancer: one disease or many. Hum Hered. 2018;83(2):65–70.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Potiron VA, Roche J, Drabkin HA. Semaphorins and their receptors in lung cancer. Cancer Lett. 2009;273(1):1–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Vergnenègre A, Chouaïd C. Review of economic analyses of treatment for non-small–cell lung cancer (NSCLC). Expert review of pharmacoeconomics & outcomes research. 2018(just-accepted).Google Scholar
  5. 5.
    Mohanty C, Das M, Kanwar JR, Sahoo SK. Receptor mediated tumor targeting: an emerging approach for cancer therapy. Curr Drug Deliv. 2011;8(1):45–58.PubMedCrossRefGoogle Scholar
  6. 6.
    Tovar I, Expósito J, Jaén J, Alonso E, Martínez M, Guerrero R, et al. Pattern of use of radiotherapy for lung cancer: a descriptive study. BMC Cancer. 2014;14(1):697.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Lamelas IP, Arca JA, Pérez JLF. Directed therapies in lung cancer: new hope? Arch Bronconeumol (English Edition). 2012;48(10):367–71.CrossRefGoogle Scholar
  8. 8.
    Słodkowska J, Rojo MG. Digital pathology in personalized cancer therapy. Folia Histochem Cytobiol. 2011;49(4):570–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Pinho L, Mendes F, Rodrigues M, Estrela J, Teixo R. Molecular targets in lung cancer therapy: a current review. J Integr Oncol. 2015;4(148):2.Google Scholar
  10. 10.
    Liu T-C, Jin X, Wang Y, Wang K. Role of epidermal growth factor receptor in lung cancer and targeted therapies. Am J Cancer Res. 2017;7(2):187.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Shi H, Guo J, Li C, Wang Z. A current review of folate receptor alpha as a potential tumor target in non-small-cell lung cancer. Drug Des Devel Ther. 2015;9:4989.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu S, Li S, Hai J, Wang X, Chen T, Quinn MM, et al. Targeting HER2 aberrations in non–small cell lung cancer with osimertinib. Clin Cancer Res. 2018;24:2594–604.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Takenaka M, Hanagiri T, Shinohara S, Kuwata T, Chikaishi Y, Oka S, et al. The prognostic significance of HER2 overexpression in non-small cell lung cancer. Anticancer Res. 2011;31(12):4631–6.PubMedGoogle Scholar
  14. 14.
    Ukrainskaya V, Stepanov A, Glagoleva I, Knorre V, Belogurov A, Gabibov A. Death receptors: new opportunities in cancer therapy. Acta Naturae (англоязычная версия). 2017;9(3):55–63.CrossRefGoogle Scholar
  15. 15.
    Spierings DC, de Vries EG, Timens W, Groen HJ, Boezen HM, de Jong S. Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumors. Clin Cancer Res. 2003;9(9):3397–405.PubMedGoogle Scholar
  16. 16.
    Vences-Catalán F, Levy S. Immune targeting of tetraspanins involved in cell invasion and metastasis. Front Immunol. 2018;9:1277.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kwon MJ, Seo J, Kim YJ, Kwon MJ, Choi JY, Kim T-E, et al. Prognostic significance of CD151 overexpression in non-small cell lung cancer. Lung Cancer. 2013;81(1):109–16.PubMedCrossRefGoogle Scholar
  18. 18.
    Li P, Zeng H, Qin J, Zou Y, Peng D, Zuo H, et al. Effects of tetraspanin CD151 inhibition on A549 human lung adenocarcinoma cells. Mol Med Rep. 2015;11(2):1258–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Drilon A, Cappuzzo F, Ou S-HI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12(1):15–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Hsu L-H, Chu N-M, Kao S-H. Estrogen, estrogen receptor and lung cancer. Int J Mol Sci. 2017;18(8):1713.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Jacenik D, Cygankiewicz AI, Krajewska WM. The G protein-coupled estrogen receptor as a modulator of neoplastic transformation. Mol Cell Endocrinol. 2016;429:10–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Ishibashi H, Suzuki T, Suzuki S, Niikawa H, Lu L, Miki Y, et al. Progesterone receptor in non–small cell lung cancer—a potent prognostic factor and possible target for endocrine therapy. Cancer Res. 2005;65(14):6450–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Choudhary R, Li H, Winn RA, Sorenson AL, Weiser-Evans MC, Nemenoff RA. Peroxisome proliferator-activated receptor-γ inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail. Neoplasia. 2010;12(3):224–34.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lapa C, Hänscheid H, Wild V, Pelzer T, Schirbel A, Werner RA, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. 2016;7(15):20033.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Callison JC, Walker RC, Massion PP. Somatostatin receptors in lung cancer: from function to molecular imaging and therapeutics. J Lung Cancer. 2011;10(2):69–76.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, et al. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci. 2002;99(6):3657–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Liang W-C, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y, et al. Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol. 2007;366(3):815–29.PubMedCrossRefGoogle Scholar
  29. 29.
    Narazaki M, Segarra M, Tosato G. Sulfated polysaccharides identified as inducers of neuropilin-1 internalization and functional inhibition of VEGF165 and semaphorin3A. Blood. 2008;111(8):4126–36.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hallberg B, Palmer R. The role of the ALK receptor in cancer biology. Ann Oncol. 2016;27(suppl_3):iii4–iii15.PubMedCrossRefGoogle Scholar
  31. 31.
    Frezzetti D, Gallo M, Maiello MR, D’Alessio A, Esposito C, Chicchinelli N, et al. VEGF as a potential target in lung cancer. Expert Opin Ther Targets. 2017;21(10):959–66.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu B, Ma Y, Yang Y, Zhang L, Han H, Chen J. CD44 promotes cell proliferation in non-small cell lung cancer. Oncol Lett. 2018;15(4):5627–33.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Penno MB, August JT, Baylin SB, Mabry M, Linnoila RI, Lee VS, et al. Expression of CD44 in human lung tumors. Cancer Res. 1994;54(5):1381–7.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Teicher BA. Targets in small cell lung cancer. Biochem Pharmacol. 2014;87(2):211–9.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Moreno P, Ramos-Álvarez I, Moody TW, Jensen RT. Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets. 2016;20(9):1055–73.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Shiao T-H, Chang Y-L, Yu C-J, Chang Y-C, Hsu Y-C, Chang S-H, et al. Epidermal growth factor receptor mutations in small cell lung cancer: a brief report. J Thorac Oncol. 2011;6(1):195–8.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2(1):48.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Bakker J, Spits M, Neefjes J, Berlin I. The EGFR odyssey–from activation to destruction in space and time. J Cell Sci. 2017;130(24):4087–96.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Zeng F, Wang Y, Kloepfer LA, Wang S, Harris RC. ErbB4 deletion predisposes to development of metabolic syndrome in mice. Am J Physiol Endocrinol Metab. 2018;315:E583.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Chen J, Zeng F, Forrester SJ, Eguchi S, Zhang M-Z, Harris RC. Expression and function of the epidermal growth factor receptor in physiology and disease. Physiol Rev. 2016;96(3):1025–69.CrossRefGoogle Scholar
  41. 41.
    Cohen BD, Kiener PA, Green JM, Foy L, Fell HP, Zhang K. The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells. J Biol Chem. 1996;271(48):30897–903.PubMedCrossRefGoogle Scholar
  42. 42.
    Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 1996;15(10):2452–67.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Dawson JP, Berger MB, Lin C-C, Schlessinger J, Lemmon MA, Ferguson KM. Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol. 2005;25(17):7734–42.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Mouse H. Epidermal growth factor. 1992.Google Scholar
  45. 45.
    McClintock JL, Ceresa BP. Transforming growth factor-α enhances corneal epithelial cell migration by promoting EGFR recycling. Invest Ophthalmol Vis Sci. 2010;51(7):3455–61.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Normanno N, Bianco C, De Luca A, Maiello M, Salomon D. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer. 2003;10(1):1–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74.PubMedCrossRefGoogle Scholar
  48. 48.
    Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6(4):443.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Mazzarella L, Guida A, Curigliano G. Cetuximab for treating non-small cell lung cancer. Expert Opin Biol Ther. 2018;18(4):483–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Pirker R, Filipits M. Monoclonal antibodies against EGFR in non-small cell lung cancer. Crit Rev Oncol Hematol. 2011;80(1):1–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Reck M, Socinski MA, Luft A, Szczęsna A, Dediu M, Ramlau R, et al. The effect of necitumumab in combination with gemcitabine plus cisplatin on tolerability and on quality of life: results from the phase 3 SQUIRE trial. J Thorac Oncol. 2016;11(6):808–18.PubMedCrossRefGoogle Scholar
  53. 53.
    Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol. 2002;20(1):110–24.PubMedCrossRefGoogle Scholar
  54. 54.
    Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002;62(20):5749–54.PubMedGoogle Scholar
  55. 55.
    Di Gennaro E, Barbarino M, Bruzzese F, De Lorenzo S, Caraglia M, Abbruzzese A, et al. Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells. J Cell Physiol. 2003;195(1):139–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001;7(5):1459–65.PubMedGoogle Scholar
  57. 57.
    Sebastian M, Schmittel A, Reck M. First-line treatment of EGFR-mutated nonsmall cell lung cancer: critical review on study methodology. Eur Respir Rev. 2014;23(131):92–105.PubMedCrossRefGoogle Scholar
  58. 58.
    Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al. SATURN: a double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27(15_suppl):8001.Google Scholar
  59. 59.
    Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60(1):15–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Dey N, Leyland-Jones B, De P. HER2 signaling network in advanced breast cancer: opportunities for combination therapies. In: PI3K-mTOR cancer and cancer therapy. Cham: Springer; 2016. p. 231–61.Google Scholar
  61. 61.
    Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan–human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non–small-cell lung cancer. J Clin Oncol. 2012;30(27):3337.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kim D-W, Tiseo M, Ahn M-J, Reckamp KL, Hansen KH, Kim S-W, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Shi Y, Zhang L, Liu X, Zhou C, Zhang S, Wang D, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013;14(10):953–61.PubMedCrossRefGoogle Scholar
  64. 64.
    Ayeni D, Politi K, Goldberg SB. Emerging agents and new mutations in EGFR-mutant lung cancer. Clin Cancer Res. 2015:clincanres. 1211.2015.Google Scholar
  65. 65.
    Liao B-C, Lin C-C, Lee J-H, Yang JC-H. Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors. J Biomed Sci. 2016;23(1):86.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Food, Administration D. Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations. Food and Drug Administration2011Class Labeling Changes to Anti-EGFR Monoclonal Antibodies, Cetuximab (Erbitux) and Panitumumab (Vectibix): KRAS Mutations. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm172905.htm Accessed 2011;7.
  67. 67.
    van Bueren JJL, Bleeker WK, Brännström A, von Euler A, Jansson M, Peipp M, et al. The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra-and intermolecular flexibility. Proc Natl Acad Sci. 2008;105(16):6109–14.CrossRefGoogle Scholar
  68. 68.
    Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Zitvogel L, et al. Trial watch: tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology. 2014;3(1):e27048.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Rodriguez PC, Neninger E, García B, Popa X, Viada C, Luaces P, et al. Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an Epidermal Growth Factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients. J Immune Based Ther Vaccines. 2011;9(1):7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Danson S, Ward TH, Butler J, Ranson M. DT-diaphorase: a target for new anticancer drugs. Cancer Treat Rev. 2004;30(5):437–49.PubMedCrossRefGoogle Scholar
  71. 71.
    Hargreaves R, Hartley JA, Butler J. Mechanisms of action of quinone-containing alkylating agents: DNA alkylation by aziridinylquinones. Front Biosci. 2000;5:E172–E80.PubMedCrossRefGoogle Scholar
  72. 72.
    Sundarraj S, Thangam R, Sujitha MV, Vimala K, Kannan S. Ligand-conjugated mesoporous silica nanorattles based on enzyme targeted prodrug delivery system for effective lung cancer therapy. Toxicol Appl Pharmacol. 2014;275(3):232–43.PubMedCrossRefGoogle Scholar
  73. 73.
    Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394(6692):485.PubMedCrossRefGoogle Scholar
  74. 74.
    Iida H, Suzuki M, Goitsuka R, Ueno H. Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2. Int J Oncol. 2012;40(1):71–9.PubMedGoogle Scholar
  75. 75.
    Liu Y, Song X, Wang X, Wei L, Liu X, Yuan S, et al. Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells. J Cell Biochem. 2010;111(3):554–63.PubMedCrossRefGoogle Scholar
  76. 76.
    Wohlkoenig C, Leithner K, Deutsch A, Hrzenjak A, Olschewski A, Olschewski H. Hypoxia-induced cisplatin resistance is reversible and growth rate independent in lung cancer cells. Cancer Lett. 2011;308(2):134–43.PubMedCrossRefGoogle Scholar
  77. 77.
    Minakata K, Takahashi F, Nara T, Hashimoto M, Tajima K, Murakami A, et al. Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors. Cancer Sci. 2012;103(11):1946–54.PubMedCrossRefGoogle Scholar
  78. 78.
    Patterson AV, Silva S, Guise C, Abbattista M, Bull M, Hsu H-L, et al. The hypoxia-activated EGFR-TKI TH-4000 overcomes erlotinib-resistance in preclinical NSCLC models at plasma levels achieved in a phase 1 clinical trial. AACR. 2015.Google Scholar
  79. 79.
    Patterson AV, Silva S, Guise C, Bull M, Abbattista M, Hsu A, et al. TH-4000, a hypoxia-activated EGFR/Her2 inhibitor to treat EGFR-TKI resistant T790M-negative NSCLC. Am Soc Clin Oncol. 2015;33:e13548.CrossRefGoogle Scholar
  80. 80.
    Salgia R. MET in lung cancer: biomarker selection based on scientific rationale. Mol Cancer Ther. 2017;16(4):555–65.PubMedCrossRefGoogle Scholar
  81. 81.
    Song X, Han X, Yu F, Zhang X, Chen L, Lv C. Polyamine-targeting gefitinib prodrug and its near-infrared fluorescent theranostic derivative for monitoring drug delivery and lung cancer therapy. Theranostics. 2018;8(8):2217.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Ashton JR, Gottlin EB, Patz EF Jr, West JL, Badea CT. A comparative analysis of EGFR-targeting antibodies for gold nanoparticle CT imaging of lung cancer. PLoS One. 2018;13(11):e0206950.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wan J, Wu W, Zhang R, Liu S, Huang Y. Anti-EGFR antibody conjugated silica nanoparticles as probes for lung cancer detection. Exp Ther Med. 2017;14(4):3407–12.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Qian Y, Qiu M, Wu Q, Tian Y, Zhang Y, Gu N, et al. Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles. Sci Rep. 2014;4:7490.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Maya S, Sarmento B, Lakshmanan V-K, Menon D, Seabra V, Jayakumar R. Chitosan cross-linked docetaxel loaded EGF receptor targeted nanoparticles for lung cancer cells. Int J Biol Macromol. 2014;69:532–41.PubMedCrossRefGoogle Scholar
  86. 86.
    Patel J, Amrutiya J, Bhatt P, Javia A, Jain M, Misra A. Targeted delivery of monoclonal antibody conjugated docetaxel loaded PLGA nanoparticles into EGFR overexpressed lung tumour cells. J Microencapsul. 2018;35(2):204–17.PubMedCrossRefGoogle Scholar
  87. 87.
    Cheng L, Huang F-Z, Cheng L-F, Zhu Y-Q, Hu Q, Li L, et al. GE11-modified liposomes for non-small cell lung cancer targeting: preparation, ex vitro and in vivo evaluation. Int J Nanomedicine. 2014;9:921.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Gill KK, Kamal MM, Kaddoumi A, Nazzal S. EGFR targeted delivery of paclitaxel and parthenolide co-loaded in PEG-Phospholipid micelles enhance cytotoxicity and cellular uptake in non-small cell lung cancer cells. J Drug Delivery Sci Technol. 2016;36:150–5.CrossRefGoogle Scholar
  89. 89.
    Lawrence RE, Salgia R. MET molecular mechanisms and therapies in lung cancer. Cell Adh Migr. 2010;4(1):146–52.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Salgia R, editor. Role of c-Met in cancer: emphasis on lung cancer. Seminars in oncology. Elsevier; 2009.Google Scholar
  91. 91.
    Skead G, Govender D. Gene of the month: MET. J Clin Pathol. 2015;68(6):405–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Porter J. Small molecule c-Met kinase inhibitors: a review of recent patents. Expert Opin Ther Pat. 2010;20(2):159–77.PubMedCrossRefGoogle Scholar
  93. 93.
    Sattler M, Hasina R, Reddy MM, Gangadhar T, Salgia R. The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol. 2011;3(4):171–84.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Birchmeier C, Birchmeier W, Gherardi E, Woude GFV. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4(12):915.PubMedCrossRefGoogle Scholar
  95. 95.
    Zhang YW, Woude GFV. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem. 2003;88(2):408–17.PubMedCrossRefGoogle Scholar
  96. 96.
    Organ SL, Tsao M-S. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1_suppl):S7–S19.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF β-chain in complex with the Sema domain of the Met receptor. EMBO J. 2004;23(12):2325–35.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Gherardi E, Sandin S, Petoukhov MV, Finch J, Youles ME, Öfverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci. 2006;103(11):4046–51.PubMedCrossRefGoogle Scholar
  99. 99.
    Maulik G, Madhiwala P, Brooks S, Ma P, Kijima T, Tibaldi E, et al. Activated c-Met signals through PI3K with dramatic effects on cytoskeletal functions in small cell lung cancer. J Cell Mol Med. 2002;6(4):539–53.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 2003;63(19):6272–81.PubMedGoogle Scholar
  101. 101.
    Sattler M, Ma PC, Salgia R. Therapeutic targeting of the receptor tyrosine kinase Met. In: Molecular targeting and signal transduction. Boston: Springer; 2004. p. 121–38.CrossRefGoogle Scholar
  102. 102.
    Otsuka T, Jakubczak J, Vieira W, Bottaro DP, Breckenridge D, Larochelle WJ, et al. Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis. Mol Cell Biol. 2000;20(6):2055–65.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, et al. NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor. Blood. 2007;109(7):3042–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Meng Y, Lin YL, Roux B. Computational study of the “DFG-flip” conformational transition in c-Abl and c-Src tyrosine kinases. J Phys Chem B. 2015;119(4):1443–56.PubMedCrossRefGoogle Scholar
  105. 105.
    Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007;67(9):4408–17.PubMedCrossRefGoogle Scholar
  106. 106.
    Wang X, Le P, Liang C, Chan J, Kiewlich D, Miller T, et al. Potent and selective inhibitors of the Met (hepatocyte growth factor/scatter factor (HGF/SF) receptor) tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther. 2003;2(11):1085–92.PubMedGoogle Scholar
  107. 107.
    Mughal A, Aslam HM, Sheikh A, Khan AMH, Saleem S. c-Met inhibitors. Infect Agents Cancer. 2013;8(1):13.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Hiscox S, Jordan NJ, Jiang W, Harper M, McClelland R, Smith C, et al. Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour–stroma interactions. Endocr Relat Cancer. 2006;13(4):1085–99.PubMedCrossRefGoogle Scholar
  109. 109.
    Mekhail T, Rich T, Rosen L, Chai F, Semic-Suka Z, Savage R, et al. Final results: a dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors. J Clin Oncol. 2009;27(15S):3548.Google Scholar
  110. 110.
    Timofeevski SL, McTigue MA, Ryan K, Cui J, Zou HY, Zhu JX, et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry. 2009;48(23):5339–49.PubMedCrossRefGoogle Scholar
  111. 111.
    Perera T, Lavrijssen T, Janssens B, Geerts T, King P, Mevellec L et al. JNJ-38877605: a selective Met kinase inhibitor inducing regression of Met-driven tumor models. AACR; 2008.Google Scholar
  112. 112.
    Salgia R, Hong D, Camacho L, Ng C, Janisch L, Ratain M, et al. A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies. J Clin Oncol. 2007;25(18_suppl):14031.Google Scholar
  113. 113.
    Giordano S. Rilotumumab, a mAb against human hepatocyte growth factor for the treatment of cancer. Curr Opin Mol Ther. 2009;11(4):448–55.PubMedGoogle Scholar
  114. 114.
    Merchant M, Zheng Z, Romero M, Huang A, Adams C, Moffat B et al. One-armed 5D5 (OA5D5) is a potent humanized HGF-blocking anti-c-Met monovalent antibody that inhibits HGF-dependent activity in vitro and demonstrates anti-tumor efficacy in vivo. AACR; 2007.Google Scholar
  115. 115.
    Underiner TL, Herbertz T, Miknyoczki SJ. Discovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates. Anticancer Agents Med Chem. 2010;10(1):7–27.PubMedCrossRefGoogle Scholar
  116. 116.
    Lu R-M, Chang Y-L, Chen M-S, Wu H-C. Single chain anti-c-Met antibody conjugated nanoparticles for in vivo tumor-targeted imaging and drug delivery. Biomaterials. 2011;32(12):3265–74.PubMedCrossRefGoogle Scholar
  117. 117.
    Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T, et al. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther. 2007;14(11):894.PubMedCrossRefGoogle Scholar
  118. 118.
    Chen Y, Mathy NW, Lu H. The role of VEGF in the diagnosis and treatment of malignant pleural effusion in patients with non-small cell lung cancer. Mol Med Rep. 2018;17(6):8019–30.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Vázquez S, Anido U, Lázaro M, Santomé L, Afonso J, Fernández O, et al. Angiogenesis and lung cancer. In: Oncogenesis, inflammatory and parasitic tropical diseases of the lung. Croatia: InTech; 2013.Google Scholar
  120. 120.
    Herbst RS, Onn A, Sandler A. Angiogenesis and lung cancer: prognostic and therapeutic implications. J Clin Oncol. 2005;23(14):3243–56.PubMedCrossRefGoogle Scholar
  121. 121.
    Hall RD, Le TM, Haggstrom DE, Gentzler RD. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2015;4(5):515.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. 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. 2004;22(11):2184–91.PubMedCrossRefGoogle Scholar
  123. 123.
    Doebele RC, Spigel D, Tehfe M, Thomas S, Reck M, Verma S, et al. Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non–small cell lung cancer. Cancer. 2015;121(6):883–92.PubMedCrossRefGoogle Scholar
  124. 124.
    Blumenschein GR, Saintigny P, Liu S, Kim ES, Tsao AS, Herbst RS, et al. Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. Clin Cancer Res. 2013;19(24):6967–75.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Dingemans A-MC, Mellema WW, Groen HJ, Van Wijk A, Burgers SA, Kunst PW, et al. A phase II study of sorafenib in patients with platinum-pretreated, advanced (stage IIIb or IV) non–small cell lung cancer with a KRAS mutation. Clin Cancer Res. 2013;19(3):743–51.PubMedCrossRefGoogle Scholar
  126. 126.
    Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60(8):2178–89.PubMedGoogle Scholar
  127. 127.
    Scagliotti G, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012;2012:2829–36.CrossRefGoogle Scholar
  128. 128.
    Kubota K, Ichinose Y, Scagliotti G, Spigel D, Kim J, Shinkai T, et al. Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis. Ann Oncol. 2014;25(2):529–36.PubMedCrossRefGoogle Scholar
  129. 129.
    Reck M, Kaiser R, Mellemgaard A, Douillard J-Y, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2):143–55.PubMedCrossRefGoogle Scholar
  130. 130.
    Bukowski RM. AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs. 2003;12(8):1403–11.PubMedCrossRefGoogle Scholar
  131. 131.
    Kim SH, Jeong JH, Lee SH, Kim SW, Park TG. Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. J Control Release. 2008;129(2):107–16.PubMedCrossRefGoogle Scholar
  132. 132.
    Sundaram S, Trivedi R, Durairaj C, Ramesh R, Ambati BK, Kompella UB. Targeted drug and gene delivery systems for lung cancer therapy. Clin Cancer Res. 2009;15:7299–308.  https://doi.org/10.1158/1078-0432.CCR-09-1745.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Zhang L, Liu Z, Yang K, Kong C, Liu C, Chen H, et al. Tumor progression of non-small cell lung cancer controlled by albumin and micellar nanoparticles of itraconazole, a multitarget angiogenesis inhibitor. Mol Pharm. 2017;14(12):4705–13.PubMedCrossRefGoogle Scholar
  134. 134.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.PubMedCrossRefGoogle Scholar
  135. 135.
    Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009;119(10):3000–10.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Jänne PA, Yang JC-H, Kim D-W, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.PubMedCrossRefGoogle Scholar
  138. 138.
    Mokhtari RB, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022.PubMedCentralCrossRefPubMedGoogle Scholar
  139. 139.
    Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046–54.PubMedCrossRefGoogle Scholar
  140. 140.
    Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2012;24(1):75–83.PubMedCrossRefGoogle Scholar
  141. 141.
    Pirker R, Szczesna A, Von Pawel J, Krzakowski M, Ramlau R, Park K, et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(15_suppl):3.CrossRefGoogle Scholar
  142. 142.
    Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330–6.  https://doi.org/10.1158/0008-5472.CAN-08-4597.CrossRefPubMedGoogle Scholar
  143. 143.
    Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non–small-cell lung cancer. J Clin Oncol. 2010;28(1):56.PubMedCrossRefGoogle Scholar
  144. 144.
    Heigener DF, Pereira JR, Felip E, Mazal J, Manzyuk L, Tan EH, et al. Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial. Target Oncol. 2015;10(2):255–65.PubMedCrossRefGoogle Scholar
  145. 145.
    Pirker R, Pereira JR, Szczesna A, Von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525–31.PubMedCrossRefGoogle Scholar
  146. 146.
    Kim ES, Neubauer M, Cohn A, Schwartzberg L, Garbo L, Caton J, et al. Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Lancet Oncol. 2013;14(13):1326–36.PubMedCrossRefGoogle Scholar
  147. 147.
    Al-Farsi A, Ellis PM. Treatment paradigms for patients with metastatic non-small cell lung cancer, squamous lung cancer: first, second, and third-line. Front Oncol. 2014;4:157.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Kim HR, Jang JS, Sun J-M, Ahn M-J, Kim D-W, Jung I, et al. A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01). Oncotarget. 2017;8(9):15943.PubMedGoogle Scholar
  149. 149.
    Blumenschein G Jr, Sandler A, O’rourke T, Eschenberg M, Sun Y, Gladish G, et al. Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2006;24(18_suppl):7119.Google Scholar
  150. 150.
    Registry IGCT. A phase II trial of carboplatin, pemetrexed, and panitumumab in patients with advanced non-squamous K-ras wild type non-small-cell lung cancer carboplatin, pemetrexed, and panitumumab in patients with advanced non-squamous K-ras wild type NSCLC. https://ichgcp.net/clinical-trials-registry/NCT01042288. Accessed 26 Jan 2019.
  151. 151.
    Hughes B, Mileshkin L, Townley P, Gitlitz B, Eaton K, Mitchell P, et al. Pertuzumab and erlotinib in patients with relapsed non-small cell lung cancer: a phase II study using 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Oncologist. 2014;19(2):175–6.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Medicine USNLo. Safety and effect of pertuzumab in patients with advanced non-small cell lung cancer, which has progressed after prior chemotherapy. https://clinicaltrials.gov/ct2/show/NCT00063154. Accessed 26 Jan 2019.
  153. 153.
    Medicine USNlo. A study of gemcitabine-cisplatin chemotherapy plus necitumumab in the first-line treatment of participants with squamous lung cancer. https://clinicaltrials.gov/ct2/show/NCT01788566. Accessed 26 Jan 2019.
  154. 154.
    Medicine USNLo. A study of trastuzumab emtansine in participants with human epidermal growth factor receptor (HER)2 immunohistochemistry (IHC)-positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC).Google Scholar
  155. 155.
    Costa DB, Shaw AT, Ou S-HI, Solomon BJ, Riely GJ, Ahn M-J, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non–small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046–61. CD-14-0337.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46.PubMedCrossRefGoogle Scholar
  159. 159.
    Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–508.PubMedCrossRefGoogle Scholar
  160. 160.
    Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–42.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences &TechnologyInstitute of Chemical Technology, MatungaMumbaiIndia
  2. 2.Department of Pharmaceutical SciencesInsitute of Chemical Technology, Deemed University, Elite Status and Centre of Excellence, Government of MaharashtraMumbaiIndia
  3. 3.Department of Chemical EngineeringInstitute of Chemical Technology, MatungaMumbaiIndia

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