The rapid expansion of novel technologies in cancer research over the past several years has led to a dramatically improved understanding of the molecular biology of lung cancer. As a consequence, novel targeted therapies are rapidly being developed. In this review, we summarize the most important molecular pathways in lung cancer and describe the clinical evidence for the development of therapies against these targets.
BelinskyS.A.NikulaK.J.PalmisanoW.A.MichelsR.SaccomannoG.GabrielsonE. (1998) Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A95: 11891–11896.
2.
BelinskyS.A.PalmisanoW.A.GillilandF.D.CrooksL.A.DivineK.K.WintersS.A. (2002) Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res62: 2370–2377.
3.
BellD.W.LynchT.J.HaserlatS.M.HarrisP.L.OkimotoR.A.BranniganB.W. (2005) Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol23: 8081–8092.
4.
BezjakA.TuD.SeymourL.ClarkG.TrajkovicA.ZukinM. (2006) Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol24: 3831–3837.
5.
BroseM.S.VolpeP.FeldmanM.KumarM.RishiI.GerreroR. (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res62: 6997–7000.
6.
CappuzzoF.CiuleanuT.StelmakhL.CicenasS.SzczesnaA.JuhaszE. (2010) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol11: 521–529.
7.
ChangA.ParikhP.ThongprasertS.TanE.H.PerngR.P.GanzonD. (2006) Gefitinib (IRESSA) in patients of Asian origin with refractory advanced non-small cell lung cancer: subset analysis from the ISEL study. J Thorac Oncol1: 847–855.
8.
ChangG.C.HsuS.L.TsaiJ.R.LiangF.P.LinS.Y.SheuG.T. (2004) Molecular mechanisms of ZD1839-induced G1-cell cycle arrest and apoptosis in human lung adenocarcinoma A549 cells. Biochem Pharmacol68: 1453–1464.
9.
ChenZ.SasakiT.TanX.CarreteroJ.ShimamuraT.LiD. (2010) Inhibition of ALK, PI3K/MEK and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene. Cancer Res70: 9827–9836.
10.
CiuleanuT.BrodowiczT.ZielinskiC.KimJ.H.KrzakowskiM.LaackE. (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. Lancet374: 1432–1440.
11.
CrinoL.DansinE.GarridoP.GriesingerF.LaskinJ.PavlakisN. (2010) Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol11: 733–740.
12.
DamianiL.A.YinglingC.M.LengS.RomoP.E.NakamuraJ.BelinskyS.A. (2008) Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res68: 9005–9014.
13.
De BoerR.ArrietaÓ.GottfriedM.BlackhallF.H.RaatsJ.YangC.H. (2009) Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL). J Clin Oncol27(15 Suppl.): 8010.
14.
DouillardJ.Y.ShepherdF.A.HirshV.MokT.SocinskiM.A.GervaisR. (2010) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol28: 744–752.
15.
EngelmanJ.A.ZejnullahuK.MitsudomiT.SongY.HylandC.ParkJ.O. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science316: 1039–1043.
16.
FisherG.H.WellenS.L.KlimstraD.LenczowskiJ.M.TichelaarJ.W.LizakM.J. (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev15: 3249–3262.
17.
FolkmanJ.MerlerE.AbernathyC.WilliamsG. (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med133: 275–288.
18.
FongP.C.BossD.S.YapT.A.TuttA.WuP.Mergui-RoelvinkM. (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med361: 123–134.
19.
FukuokaM.YanoS.GiacconeG.TamuraT.NakagawaK.DouillardJ.Y. (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 Oncol21: 2237–2246.
20.
GandaraD.KimE.S.HerbstR.S.MoonJ.RedmanM.W.DakhilS.R. (2010) S0536: Carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC): A SWOG phase II study. J Clin Oncol27(15 Suppl.): 8015.
21.
GatzemeierU.PluzanskaA.SzczesnaA.KaukelE.RoubecJ.De RosaF. (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol25: 1545–1552.
22.
GiacconeG.HerbstR.S.ManegoldC.ScagliottiG.RosellR.MillerV. (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol22: 777–784.
23.
GossG.D.LorimerI.TsaoM.S.O’CallaghanC.J.DingK.MastersG.A. (2010) A phase III randomized, double-blind, placebo controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB–IIIA NSCLC. In: Proceedings of the ASCO 2010, Chicago. J Clin Oncol28(Suppl.): 18s.
24.
HerbstR.S.GiacconeG.SchillerJ.H.NataleR.B.MillerV.ManegoldC. (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol22: 785–794.
25.
HerbstR.S.O’NeillV.J.FehrenbacherL.BelaniC.P.BonomiP.D.HartL. (2007) Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol25: 4743–4750.
26.
HerbstR.S.PragerD.HermannR.FehrenbacherL.JohnsonB.E.SandlerA. (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol23: 5892–5899.
27.
HerbstR.S.SunY.EberhardtW.E.GermonpreP.SaijoN.ZhouC. (2010) Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol11: 619–626.
28.
HermanJ.G.BaylinS.B. (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med349: 2042–2054.
29.
HirschF.R.Varella-GarciaM.BunnP.A.JrFranklinW.A.DziadziuszkoR.ThatcherN. (2006) Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol24: 5034–5042.
30.
JanneP.A.von PawelJ.CohenR.B.CrinoL.ButtsC.A.OlsonS.S. (2007) Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small-cell lung cancer. J Clin Oncol25: 3936–3944.
31.
JanneP.A.WangX.F.SocinskiM.A.CrawfordJ.CapellettiM.EdelmanM.J. (2010) Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406. J Clin Oncol28(15 Suppl.): 7503.
32.
JassemJ.LangerC.J.KarpD.D.MokT.BennerR.J.GreenS.J. (2010) Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). J Clin Oncol28(15 Suppl.): 7500.
33.
JemalA.SiegelR.XuJ.WardE. (2010) Cancer statistics, 2010. CA Cancer J Clin60: 277–300.
34.
JiH.LiD.ChenL.ShimamuraT.KobayashiS.McNamaraK. (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell9: 485–495.
35.
JohnsonD.H.FehrenbacherL.NovotnyW.F.HerbstR.S.NemunaitisJ.J.JablonsD.M. (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 Oncol22: 2184–2191.
36.
KarpD.D.Paz-AresL.G.NovelloS.HaluskaP.GarlandL.CardenalF. (2009) Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol27: 2516–2522.
37.
KeckP.J.HauserS.D.KriviG.SanzoK.WarrenT.FederJ. (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science246: 1309–1312.
38.
KellyK.ChanskyK.GasparL.E.AlbainK.S.JettJ.UngY.C. (2008) Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol26: 2450–2456.
39.
Khambata-FordS.HarbisonC.T.HartL.L.AwadM.XuL.A.HorakC.E. (2010) Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol28: 918–927.
40.
KimE.S.HirshV.MokT.SocinskiM.A.GervaisR.WuY.L. (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet372: 1809–1818.
41.
KoivunenJ.P.MermelC.ZejnullahuK.MurphyC.LifshitsE.HolmesA.J. (2008) EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res14: 4275–4283.
42.
KrisM.G.NataleR.B.HerbstR.S.LynchT.J.JrPragerD.BelaniC.P. (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA290: 2149–2158.
43.
KwakE.L.BangY.J.CamidgeD.R.ShawA.T.SolomonB.MakiR.G. (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med363: 1693–1703.
44.
LeeL.HirshV.ParkK.QinnS.PlajmanC.R.PerngR. (2010) Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): A randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol28(25 Suppl.): 7525.
45.
LeidnerR.S.FuP.CliffordB.HamdanA.JinC.EisenbergR. (2009) Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol27: 5620–5626.
46.
LeungD.W.CachianesG.KuangW.J.GoeddelD.V.FerraraN. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science246: 1306–1309.
47.
LicchesiJ.D.WestraW.H.HookerC.M.HermanJ.G. (2008a) Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung. Clin Cancer Res14: 2570–2578.
48.
LicchesiJ.D.WestraW.H.HookerC.M.MachidaE.O.BaylinS.B.HermanJ.G. (2008b) Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis29: 895–904.
49.
LynchT.J.BellD.W.SordellaR.GurubhagavatulaS.OkimotoR.A.BranniganB.W. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med350: 2129–2139.
50.
LynchT.J.PatelT.DreisbachL.McCleodM.HeimW.J.HermannR.C. (2010) Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol28: 911–917.
51.
MaemondoM.InoueA.KobayashiK.SugawaraS.OizumiS.IsobeH. (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med362: 2380–2388.
52.
McCabeM.T.BrandesJ.C.VertinoP.M. (2009) Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res15: 3927–3937.
53.
MitsudomiT.MoritaS.YatabeY.NegoroS.OkamotoI.TsurutaniJ. (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 Oncol11: 121–128.
54.
MokT.S.WuY.L.ThongprasertS.YangC.H.ChuD.T.SaijoN. (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med361: 947–957.
55.
MorgilloF.KimW.Y.KimE.S.CiardielloF.HongW.K.LeeH.Y. (2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res13: 2795–2803.
56.
MorgilloF.WooJ.K.KimE.S.HongW.K.LeeH.Y. (2006) Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res66: 10100–10111.
57.
NataleR.B.ThongprasertS.GrecoF.A.ThomasM.TsaiC.M.SunpaweravongP. (2009) Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST). J Clin Oncol27(15 Suppl.): 8009.
58.
OwonikokoT.K.RamalingamS.S.BeheraM.BrandeS.J.C.SabaN.BhimaniC. (2010) Survival impact of newly approved therapeutic agents in patients with advanced non-small cell lung cancer (NSCLC): A SEER-Medicare database analysis. J Clin Oncol28(15 Suppl.): 7633.
59.
PaezJ.G.JanneP.A.LeeJ.C.TracyS.GreulichH.GabrielS. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science304: 1497–1500.
60.
PaoW.MillerV.A.PolitiK.A.RielyG.J.SomwarR.ZakowskiM.F. (2005a) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med2: e73.
61.
PaoW.WangT.Y.RielyG.J.MillerV.A.PanQ.LadanyiM. (2005b) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS medicine2: e17.
62.
PirkerR.PereiraJ.R.SzczesnaA.von PawelJ.KrzakowskiM.RamlauR. (2009) Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet373: 1525–1531.
63.
RamalingamS.S.HarveyR.D.SabaN.OwonikokoT.K.KauhJ.ShinD.M. (2010a) Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer. Cancer116: 3903–3909.
64.
RamalingamS.S.MaitlandM.L.FrankelP.ArgirisA.E.KoczywasM.GitlitzB. (2010b) Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol28: 56–62.
65.
ReckM.von PawelJ.ZatloukalP.RamlauR.GorbounovaV.HirshV. (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol21: 1804–1809.
66.
ReckM.von PawelJ.ZatloukalP.RamlauR.GorbounovaV.HirshV. (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol27: 1227–1234.
67.
RielyG.J.KrisM.G.RosenbaumD.MarksJ.LiA.ChitaleD.A. (2008) Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res14: 5731–5734.
68.
RielyG.J.RizviN.A.KrisM.G.MiltonD.T.SolitD.B.RosenN. (2009) Randomized phase II study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with advanced non-small-cell lung cancer. J Clin Oncol27: 264–270.
69.
SandlerA.GrayR.PerryM.C.BrahmerJ.SchillerJ.H.DowlatiA. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med355: 2542–2550.
70.
ScagliottiG.NovelloS.von PawelJ.ReckM.PereiraJ.R.ThomasM. (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol28: 1835–1842.
71.
SequistL.V.BesseB.LynchT.J.MillerV.A.WongK.K.GitlitzB. (2010) Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol28: 3076–3083.
72.
ShawA.T.YeapB.Y.Mino-KenudsonM.DigumarthyS.R.CostaD.B.HeistR.S. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol27: 4247–4253.
73.
ShepherdF.A.Rodrigues PereiraJ.CiuleanuT.TanE.H.HirshV.ThongprasertS. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med353: 123–132.
74.
SocinskiM.A.LangerC.J.HuangJ.E.KolbM.M.ComptonP.WangL. (2009) Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol27: 5255–5261.
75.
SodaM.ChoiY.L.EnomotoM.TakadaS.YamashitaY.IshikawaS. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature448: 561–566.
76.
ThatcherN.ChangA.ParikhP.Rodrigues PereiraJ.CiuleanuT.von PawelJ. (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet366: 1527–1537.
77.
TolJ.KoopmanM.CatsA.RodenburgC.J.CreemersG.J.SchramaJ.G. (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med360: 563–572.
UedaM.TojiE.NunobikiO.IzumaS.OkamotoY.ToriiK. (2008) Mutational analysis of the BRAF gene in human tumor cells. Hum Cell21: 13–17.
80.
Van CutsemE.KohneC.H.HitreE.ZaluskiJ.Chang ChienC.R.MakhsonA. (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med360: 1408–1417.
81.
WeinsteinI.B.BegemannM.ZhouP.HanE.K.SgambatoA.DokiY. (1997) Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Clin Cancer Res3: 2696–2702.
82.
Wheatley-PriceP.DingK.SeymourL.ClarkG.M.ShepherdF.A. (2008) Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol26: 2350–2357.
83.
YamamotoH.ShigematsuH.NomuraM.LockwoodW.W.SatoM.OkumuraN. (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res68: 6913–6921.
84.
YunC.H.MengwasserK.E.TomsA.V.WooM.S.GreulichH.WongK.K. (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A105: 2070–2075.
85.
ZhouC.WuY.-L.ChenG.FengJ.LiuX.WangC. (2010) Efficacy results from the randomised phase III optimal (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced nonsmall-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations. Ann Oncol21(Suppl. 8): LBA 13.