Missing the Target?—Targeted Therapy in Small Cell Lung Cancer


Small cell lung cancer [SCLC] is a devastating form of cancer, with most patients harbouring extensive disease at diagnosis and survival of less than 5% at five years. Progress in novel therapies has been limited. This specialist review explores current targeted therapy options and potential areas of development.

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Purshouse, K. (2014) Missing the Target?—Targeted Therapy in Small Cell Lung Cancer. Advances in Lung Cancer, 3, 53-61. doi: 10.4236/alc.2014.33008.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] International Agency for Research on Cancer, World Health Organisation (2012) GLOBOCAN 2012—
Estimated Cancer Incidence, Mortality and Prevalence Wordwide. http://globocan.iarc.fr/Pages/fact_
[2] Ezzati, M., Henley, S.J., Lopez, A.D. and Thun, M.J. (2005) Role of Smoking in Global and Regional Cancer Epidemiology: Current Patterns and Data Needs. International Journal of Cancer, 116, 963-971. http://dx.doi.org/10.1002/ijc.21100
[3] Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D. (2011) Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69-90. http://dx.doi.org/10.3322/caac.20107
[4] Riaz, S.P., Lüchtenborg, M., Coupland, V.H., Spicer, J., Peake, M.D. and Moller, H. (2012) Trends in Incidence of Small Cell Lung Cancer and All Lung Cancer. Lung Cancer, 75, 280-284.
[5] Cancer Research UK (2012) Statistics and Outlook for Lung Cancer. http://www.cancerresearchuk.
[6] Méndez, D., Alshanqeety, O. and Warner, K.E. (2013) The Potential Impact of Smoking Control Poli-
cies on Future Global Smoking Trends. Tobacco Control, 22, 46-51. http://dx.doi.org/10.1136/tobac
[7] (2014) Ash: Ash. Action on Smoking and Health; Facts at a Glance. Smoking Statistics. http://www.ash.org.uk/files/documents/ASH_93.pdf
[8] Harris, K., Khachaturova, I., Azab, B., et al. (2012) Small Cell Lung Cancer Doubling Time and Its Effect on Clinical Presentation: A Concise Review. Clinical Medicine Insights: Oncology, 6, 199-203. http://dx.doi.org/10.4137/CMO.S9633
[9] Jackman, D.M. and Johnson, B.E. (2005) Small-Cell Lung Cancer. The Lancet, 366, 1385-1396. http://dx.doi.org/10.1016/S0140-6736(05)67569-1
[10] Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674. http://dx.doi.org/10.1016/j.cell.2011.02.013
[11] NICE Pathways (2012) Treatment for Non-Small Cell Lung Cancer. http://pathways.nice.org.uk/path
[12] Moore, A.M., Einhorn, L.H., Estes, D., Govindan, R., Axelson, J., Vinson, J., Breen, T.E., Yu, M. and Hanna, N.H. (2006) Gefitinib in Patients with Chemo-Sensitive and Chemo-Refractory Relapsed Small
Cell Cancers: A Hoosier Oncology Group Phase II Trial. Lung Cancer, 52, 93-97. http://dx.doi.org/10.
[13] Okamoto, I., Araki, J., Suto, R., Shimada, M., Nakagawa, K. and Fukuoka, M. (2006) EGFR Mutation in
Gefitinib-Responsive Small-Cell Lung Cancer. Annals of Oncology, 17, 1028-1029. http://dx.
[14] Zakowski, M.F., Ladanyi, M., Kris, M.G. and Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group (2006) EGFR Mutations in Small-Cell Lung Cancers in Patients Who Have Never Smoked. New England Journal of Medicine, 355, 213-215. http://dx.doi.org/10.1056/NEJMc053610
[15] Warshamana-Greene, G.S., Litz, J., Buchdunger, E., García-Echeverría, C., Hofmann, F. and Krystal, G.W. (2005) The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy. Clinical Cancer Research, 11, 1563-1571. http://dx.doi.org/10.1158/1078-0432.CCR-04-1544
[16] Potti, A., Moazzam, N., Ramar, K., Hanekom, D.S., Kargas, S. and Koch, M. (2003) CD117 (c-KIT) Overexpression in Patients with Extensive-Stage Small-Cell Lung Carcinoma. Annals of Oncology, 14, 894-897. http://dx.doi.org/10.1093/annonc/mdg253
[17] Lu, H.Y., Zhang, G., Cheng, Q.Y., Chen, B., Cai, J.F., Wang, X.J., Zhang, Y.P., Wang, Z., Lu, Z.Y., Xie, F.J. and Mao, W.M. (2012) Expression and Mutation of the c-Kit Gene and Correlation with Prognosis of Small Cell Lung Cancer. Oncology Letters, 4, 89-93.
[18] Schneider, B.J., Kalemkerian, G.P., Ramnath, N., Kraut, M.J., Wozniak, A.J., Worden, F.P., Ruckdeschel, J.C., Zhang, X.H., Chen, W. and Gadgeel, S.M. (2010) Phase II Trial of Imatinib Maintenance Therapy after Irinotecan and Cisplatin in Patients with c-Kit-Positive, Extensive-Stage Small-Cell Lung Cancer. Clinical Lung Cancer, 11, 223-227. http://dx.doi.org/10.3816/CLC.2010.n.028
[19] Spigel, D.R., Hainsworth, J.D., Simons, L., Meng, C., Burris III, H.A., Yardley, D.A., Grapski, R., Schreeder, M., Mallidi, P.V. and Greco, F.A. (2007) Irinotecan, Carboplatin, and Imatinib in Untreated Extensive-Stage Small-Cell Lung Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Netwo-
rk. Journal of Thoracic Oncology, 2, 854-861. http://dx.doi.org/10.1097/JTO.0b013e31814617b7
[20] Maulik, G., Kijima, T., Ma, P.C., Ghosh, S.K., Lin, J., Shapiro, G.I., Schaefer, E., Tibaldi, E., Johnson, B.E. and Salgia, R. (2002) Modulation of the c-Met/Hepatocyte Growth Factor Pathway in Small Cell Lung Cancer. Clinical Cancer Research, 8, 620-627.
[21] Heymach, J.V., Johnson, D.H., Khuri, F.R., Safran, H., Schlabach, L.L., Yunus, F., DeVore III, R.F., De Porre, P.M., Richards, H.M., Jia, X., Zhang, S. and Johnson, B.E. (2004) Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients with Sensitive Relapse Small-Cell Lung Cancer. Annals of Oncology, 15, 1187-1193. http://dx.doi.org/10.1093/annonc/mdh315
[22] Ueda, Y., Igishi, T., Hashimoto, K., Suyama, H., Araki, K., Sumikawa, T., Takeda, K., Nakazaki, H., Matsunami, K., Kodani, M., Shigeoka, Y., Matsumoto, S. and Shimizu, E. (2009) Synergistic Cell Growth Inhibition by the Combination of Amrubicin and Akt-Suppressing Tyrosine Kinase Inhibitors in Small Cell Lung Cancer Cells: Implication of c-Src and Its Inhibitor. International Journal of Oncology, 34, 689-696.
[23] Miller, A.A., Pang, H., Hodgson, L., Ramnath, N., Otterson, G.A., Kelley, M.J., Kratzke, R.A., Vokes, E.E. for the Cancer and Leukemia Group B (2010) A Phase II Study of Dasatinib in Patients with Chemosensitive Relapsed Small Cell Lung Cancer [Cancer and Leukemia Group B 30602]. Journal of Thoracic Oncology, 5, 380-384. http://dx.doi.org/10.1097/JTO.0b013e3181cee36e
[24] Pandya, K.J., Dahlberg, S., Hidalgo, M., Cohen, R.B., Lee, M.W., Schiller, J.H. and Johnson, D.H. (2007) A Randomized, Phase II Trial of Two Dose Levels of Temsirolimus [CCI-779] in Patients with Extensive-Stage Small-Cell Lung Cancer Who Have Responding or Stable Disease after Induction Chemotherapy: A Trial of the Eastern Cooperative Oncology Group [E1500]. Journal of Thoracic Oncology, 2, 1036-1041. http://dx.doi.org/10.1097/JTO.0b013e318155a439
[25] Tarhini, A., Kotsakis, A., Gooding, W., Shuai, Y., Petro, D., Friedland, D., Belani, C.P., Dacic, S. and Argiris, A. (2010) Phase II Study of Everolimus [RAD001] in Previously Treated Small Cell Lung Cancer. Clinical Cancer Research, 16, 5900-5907. http://dx.doi.org/10.1158/1078-0432.CCR-10-0802
[26] Zhang, Y. and He, J. (2013) The Development of Targeted Therapy in Small Cell Lung Cancer. Journal of Thoracic Disease, 5, 538-548.
[27] Walls, M., Baxi, S.M., Mehta, P.P., Liu, K.K.C., Zhu, J.J., Estrella, H., Li, C.Z., Zientek, M., Zong, Q., Smeal, T. and Yin, M.J. (2014) Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Se-
lective Oral PI3K Inhibitor PF-4989216. Clinical Cancer Research, 20, 631-643. http://dx.doi.org/10.1
[28] LoRusso, P.M., Rudin, C.M., Reddy, J.C., Tibes, R., Weiss, G.J., Borad, M.J., et al. (2011) Phase I Trial of Hedgehog Pathway Inhibitor Vismodegib [GDC-0449] in Patients with Refractory, Locally Advanced
or Metastatic Solid Tumors. Clinical Cancer Research, 17, 2502-2511. http://dx.doi.org/10.1158/1078
[29] Patton, J.F., Spigel, D.R., Greco, F.A., Liggett, W.H., Zubkus, J.D., Baskette, M., Schreeder, M., Woytowitz, D., Nelson, E. and Hainsworth, J.D. (2006) Irinotecan [I], Carboplatin [C], and Radiotherapy [Rt] Followed by Maintenance Bevacizumab [b] in the Treatment [tx] of Limited-Stage Small Cell Lung Cancer [LS-SCLC]: Update of a Phase II Trial of the Minnie Pearl Cancer Research Network. Journal of Clinical Oncology, 24, 7085.
[30] Ready, N.E., Dudek, A.Z., Pang, H.H., Hodgson, L.D., Graziano, S.L., Green, M.R. and Vokes, E.E. (2011) Cisplatin, Irinotecan, and Bevacizumab for Untreated Extensive-Stage Small-Cell Lung Cancer: CALGB 30306, a Phase II Study. Journal of Clinical Oncology, 29, 4436-4441. http://dx.doi.org/10.1200/JCO.2011.35.6923
[31] Spigel, D.R., Townley, P.M., Waterhouse, D.M., Fang, L., Adiguzel, I., Huang, J.E., Karlin, D.A., Faoro, L., Scappaticci, F.A. and Socinski, M.A. (2011) Randomized Phase II Study of Bevacizumab in Combination with Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer:
Results from the SALUTE Trial. Journal of Clinical Oncology, 29, 2215-2222. http://dx.doi.org/10.1200/
[32] Mountzios, G., Emmanouilidis, C., Vardakis, N., Kontopodis, E., Hatzidaki, D., Popis, E., et al. (2012) Paclitaxel Plus Bevacizumab in Patients with Chemoresistant Relapsed Small Cell Lung Cancer as Salvage Treatment: A Phase II Multicenter Study of the Hellenic Oncology Research Group. Lung Cancer, 77, 146-150. http://dx.doi.org/10.1016/j.lungcan.2012.02.002
[33] Arnold, A.M., Seymour, L., Smylie, M., Ding, K.Y., Ung, Y., Findlay, B., et al. (2007) Phase II Study of Vandetanib or Placebo in Small-Cell Lung Cancer Patients after Complete or Partial Response to Induction Chemotherapy with or without Radiation Therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. Journal of Clinical Oncology, 25, 4278-4284.
[34] Ramalingam, S.S., Belani, C.P., Mack, P.C., Vokes, E.E., Longmate, J., Govindan, R., Koczywas, M., Ivy, S.P. and Gandara, D.R. (2010) Phase II Study of Cediranib [AZD 2171], an Inhibitor of the Vascular Endothelial Growth Factor Receptor, for Second-Line Therapy of Small Cell Lung Cancer [National Cancer Institute #7097]. Journal of Thoracic Oncology, 5, 1279-1284.
[35] Rigas, J.R., Denham, C.A., Rinaldi, D., Moore, T., Smith II, J.W., Winston, R.D. and Humphrey, R. (2003) O-107 Adjuvant Targeted Therapy in Unresectable Lung Cancer: The Results of Two Randomized Placebo-Controlled Trials of Bay 12-9566, a Matrix Metalloproteinase Inhibitor [MMPI]. Lung Cancer, 41, S34. http://dx.doi.org/10.1016/S0169-5002(03)91765-X
[36] Shepherd, F.A., Giaccone, G., Seymour, L., Debruyne, C., Bezjak, A., Hirsh, V., Smylie, M., Rubin, S., Martins, H., Lamont, A., Krzakowski, M., Sadura, A. and Zee, B. (2002) Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Marimastat after Response to First-Line Chemotherapy in Patients with Small-Cell Lung Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. Journal of Clinical Oncology, 20, 4434-4439. http://dx.doi.org/10.1200/JCO.2002.02.108
[37] Pujol, J.L., Breton, J.L., Gervais, R., Tanguy, M.L., Quoix, E., David, P., Janicot, H., Westeel, V., Gameroff, S., Genève, J. and Maraninchi, D. (2007) Phase III Double-Blind, Placebo-Controlled Study of Thalidomide in Extensive-Disease Small-Cell Lung Cancer after Response to Chemotherapy: An Intergroup Study FNCLCC cleo04 IFCT 00-01. Journal of Clinical Oncology, 25, 3945-3951. http://dx.doi.org/10.1200/JCO.2007.11.8109
[38] Lee, S.M., Woll, P.J., Rudd, R., Ferry, D., O’Brien, M., Middleton, G., Spiro, S., James, L., Ali, K., Jitlal, M. and Hackshaw, A. (2009) Anti-Angiogenic Therapy Using Thalidomide Combined with Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of the National Cancer Institute, 101, 1049-1057. http://dx.doi.org/10.1093/jnci/djp200
[39] Sharma, N., Pennell, N., Nickolich, M., Halmos, B., Ma, P., Mekhail, T., Fu, P. and Dowlati, A. (2014) Phase II Trial of Sorafenib in Conjunction with Chemotherapy and as Maintenance Therapy in Extensive-Stage Small Cell Lung Cancer. Investigational New Drugs, 32, 362-368.
[40] Ready, N.E., Pang, H.H., Gu, L., Otterson, G.A., Thomas, S.P., Miller, A.A., et al. (2013) Chemotherapy with or without Maintenance Sunitinib for Untreated Extensive-Stage Small Cell Lung Cancer: A Randomized, Placebo Controlled Phase II Study CALGB 30504 [ALLIANCE]. Journal of Clinical Oncology, 31, 7506.
[41] Heist, R.S., Fain, J., Chinnasami, B., Khan, W., Molina, J., Brainerd, V., Leopold, L. and Lynch, T. (2009) A Phase I/II [P1/P2] Study of AT-101 in Combination with Topotecan[t] in Patients with Relapsed or Refractory Small Cell Lung Cancer [SCLC] after Prior Platinum-Containing First-Line Chemotherapy. Journal of Clinical Oncology, 27, 8106.
[42] Lara Jr., P.N., Chansky, K., Davies, A.M., Franklin, W.A., Gumerlock, P.H., Guaglianone, P.P., Atkins, J.N., Farneth, N., Mack, P.C., Crowley, J.J. and Gandara, D.R. (2006) Bortezomib [PS-341] in Relapsed or Refractory Extensive Stage Small Cell Lung Cancer: A Southwest Oncology Group Phase II Trial [S0327]. Journal of Thoracic Oncology, 1, 996-1001. http://dx.doi.org/10.1097/01243894-200611000-00013
[43] Gandhi, L., Chu, Q.S., Stephenson, J., Johnson, B.E., Govindan, R., Bonomi, P., Eaton, K., Fritsch, H., Munzert, G. and Socinski, M. (2009) An Open Label Phase II Trial of the Plk1 Inhibitor Bi 2536, in Patients with Sensitive Relapse Small Cell Lung Cancer [SCLC]. Journal of Clinical Oncology, 27, 8108.
[44] Prystowsky, M., Feeney, K., Kawachi, N., Montagna, C., Willmott, M., Wasson, C., Antkowiak, M., Loudig, O. and Parish, J. (2013) Inhibition of Plk1 and Cyclin B1 Expression Results in Panobinostat-
Induced G2 Delay and Mitotic Defects. Scientific Reports, 3, 2640. http://dx.doi.org/10.1038/srep026
[45] Crisanti, M.C., Wallace, A.F., Kapoor, V., Vandermeers, F., Dowling, M.L., Pereira, L.P., et al. (2009) The HDAC Inhibitor Panobinostat [LBH589] Inhibits Mesothelioma and Lung Cancer Cells in Vitro and in Vivo with Particular Efficacy for Small Cell Lung Cancer. Molecular Cancer Therapeutics, 8, 2221-2231. http://dx.doi.org/10.1158/1535-7163.MCT-09-0138
[46] Minami, T., Kijima, T., Kohmo, S., Arase, H., Otani, Y., Nagatomo, I., et al. (2013) Overcoming Chemoresistance of Small-Cell Lung Cancer through Stepwise HER2-Targeted Antibody-Dependent Cell-Mediated Cytotoxicity and VEGF-Targeted Antiangiogenesis. Scientific Reports, 3, 2669. http://dx.doi.org/10.1038/srep02669
[47] Abidin, A.Z., Garassino, M.C., Califano, R., Harle, A. and Blackhall, F. (2010) Targeted Therapies in Small Cell Lung Cancer: A Review. Therapeutic Advances in Medical Oncology, 2, 25-37. http://dx.doi.org/10.1177/1758834009356014
[48] Giaccone, G., Debruyne, C., Felip, E., Chapman, P.B., Grant, S.C., Millward, M., Thiberville, L., D’addario, G., Coens, C., Rome, L.S., Zatloukal, P., Masso, O. and Legrand, C. (2005) Phase III Study of Adjuvant Vaccination with Bec2/Bacille Calmette-Guerin in Responding Patients with Limited-Disease Small-Cell Lung Cancer (European Organisation for Research and Treatment of Cancer 0897
1-08971B; Silva Study). Journal of Clinical Oncology, 23, 6854-6864. http://dx.doi.org/10.1200/JCO.
[49] Antonia, S.J., Mirza, N., Fricke, I., Chiappori, A., Thompson, P., Williams, N., Bepler, G., Simon, G., Janssen, W., Lee, J.H., Menander, K., Chada, S. and Gabrilovich, D.I. (2006) Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer. Clinical Cancer Research, 12, 878-887.
[50] Kola, I. and Landis, K. (2004) Can the Pharmaceutical Industry Reduce Attrition Rates? Nature Reviews Drug Discovery, 3, 711-715.
[51] Carden, C.P., Sarker, D., Postel-Vinay, S., Yap, T.A., Attard, G., Banerji, U., et al. (2010) Can Molecular Biomarker-Based Patient Selection in Phase I Trials Accelerate Anticancer Drug Development? Drug Discovery Today, 15, 88-97. http://dx.doi.org/10.1016/j.drudis.2009.11.006
[52] Stratmann, A.T., Fecher, D., Wangorsch, G., Gottlich, C., Walles, T., Walles, H., Dandekar, T., Dandekar, G. and Nietzer, S.L. (2013) Establishment of a Human 3D Lung Cancer Model Based on a Biological Tissue Matrix Combined with a Boolean in Silico Model. Molecular Oncology, 8, 351-365. http://dx.doi.org/10.1016/j.molonc.2013.11.009

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