Open Access Open Access  Restricted Access Subscription Access

The many facets of lung adenocarcinoma – a disease comprising distinct molecular subgroups.

Anna Gleinig, Sabine Huth, Uta Dahmen, Olaf Dirsch


 Abstract: Lung cancer is one of the most prevalent types of cancer throughout the world and a leading cause of cancer-related deaths. Lung cancer comprises small cell and non-small cell lung cancer. The most prevalent type of non-small cell lung cancer is adenocarcinoma (AdC). 5-year survival rates of lung AdC range between 50 and 2% for stage Ia and IV, respectively.

Novel strategies to treat lung cancer focus on personalized medicine. Personalized medicine is based on a thorough molecular characterization of tumors to tailor therapy specifically to each individual patient. This principle was developed following recent advances in molecular tumor biology that lead to the detection of oncogenic driver mutations. Oncogenic driver mutations confer cancer-properties to the cell and the cancer cell depends on the oncogenic driver mutation to sustain its phenotype (oncogene addiction).

Oncogenic driver mutations can be exploited in the treatment of cancer by targeted therapies. Targeted therapies specifically attack cancer cells while causing less side effects than conventional chemotherapy.

In lung AdC, oncogenic driver mutations define distinct molecular subgroups. This review aims at presenting the 9 best characterized molecular subgroups of lung AdC. We want to illustrate 1) the respective oncogenic mechanism, 2) patient characteristics, 3) prognostic significance and 4) targeted therapy options for each subgroup.


lung adenocarcinoma, oncogenic driver mutations, targeted therapy

Full Text:


Adjei, A. A., Mauer, A., Bruzek, L., Marks, R. S., Hillman, S., Geyer, S., Hanson, L. J., Wright, J. J., Erlichman, C., Kaufmann, S. H. and Vokes, E. E. (2003). Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol, 21(9), 1760-1766. doi: 10.1200/jco.2003.09.075

Ahrendt, S. A., Decker, P. A., Alawi, E. A., Zhu Yr, Y. R., Sanchez-Cespedes, M., Yang, S. C., Haasler, G. B., Kajdacsy-Balla, A., Demeure, M. J. and Sidransky, D. (2001). Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer, 92(6), 1525-1530.

Al-Shahrabani, F., Vallbohmer, D., Angenendt, S. and Knoefel, W. T. (2014). Surgical strategies in the therapy of non-small cell lung cancer. World J Clin Oncol, 5(4), 595-603. doi: 10.5306/wjco.v5.i4.595

American Cancer Society. (2013). Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society.

Arcila, M. E., Chaft, J. E., Nafa, K., Roy-Chowdhuri, S., Lau, C., Zaidinski, M., Paik, P. K., Zakowski, M. F., Kris, M. G. and Ladanyi, M. (2012). Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res, 18(18), 4910-4918. doi: 10.1158/1078-0432.ccr-12-0912

Beau-Faller, M., Ruppert, A. M., Voegeli, A. C., Neuville, A., Meyer, N., Guerin, E., Legrain, M., Mennecier, B., Wihlm, J. M., Massard, G., Quoix, E., Oudet, P. and Gaub, M. P. (2008). MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol, 3(4), 331-339. doi: 10.1097/JTO.0b013e318168d9d4

Bergethon, K., Shaw, A. T., Ou, S. H., Katayama, R., Lovly, C. M., McDonald, N. T., Massion, P. P., Siwak-Tapp, C., Gonzalez, A., Fang, R., Mark, E. J., Batten, J. M., Chen, H., Wilner, K. D., Kwak, E. L., Clark, J. W., Carbone, D. P., Ji, H., Engelman, J. A., Mino-Kenudson, M., Pao, W. and Iafrate, A. J. (2012). ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol, 30(8), 863-870. doi: 10.1200/jco.2011.35.6345

Blackhall, F. H., Peters, S., Bubendorf, L., Dafni, U., Kerr, K. M., Hager, H., Soltermann, A., O'Byrne, K. J., Dooms, C., Sejda, A., Hernandez-Losa, J., Marchetti, A., Savic, S., Tan, Q., Thunnissen, E., Speel, E. J., Cheney, R., Nonaka, D., de Jong, J., Martorell, M., Letovanec, I., Rosell, R. and Stahel, R. A. (2014). Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project. J Clin Oncol, 32(25), 2780-2787. doi: 10.1200/jco.2013.54.5921

Cardarella, S., Ogino, A., Nishino, M., Butaney, M., Shen, J., Lydon, C., Yeap, B. Y., Sholl, L. M., Johnson, B. E. and Janne, P. A. (2013). Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res, 19(16), 4532-4540. doi: 10.1158/1078-0432.ccr-13-0657

Chaft, J. E., Arcila, M. E., Paik, P. K., Lau, C., Riely, G. J., Pietanza, M. C., Zakowski, M. F., Rusch, V., Sima, C. S., Ladanyi, M. and Kris, M. G. (2012). Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther, 11(2), 485-491. doi: 10.1158/1535-7163.mct-11-0692

Chen, D., Zhang, L. Q., Huang, J. F., Liu, K., Chuai, Z. R., Yang, Z., Wang, Y. X., Shi, D. C., Liu, Q., Huang, Q. and Fu, W. L. (2014). BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One, 9(6), e101354. doi: 10.1371/journal.pone.0101354

Chen, Y. F., Hsieh, M. S., Wu, S. G., Chang, Y. L., Shih, J. Y., Liu, Y. N., Tsai, M. F., Tsai, T. H., Yu, C. J., Yang, J. C. and Yang, P. C. (2014). Clinical and the prognostic characteristics of lung adenocarcinoma patients with ROS1 fusion in comparison with other driver mutations in East Asian populations. J Thorac Oncol, 9(8), 1171-1179. doi: 10.1097/jto.0000000000000232

Chou, T. Y., Chiu, C. H., Li, L. H., Hsiao, C. Y., Tzen, C. Y., Chang, K. T., Chen, Y. M., Perng, R. P., Tsai, S. F. and Tsai, C. M. (2005). Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res, 11(10), 3750-3757. doi: 10.1158/1078-0432.ccr-04-1981

Davies, K. D. and Doebele, R. C. (2013). Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res, 19(15), 4040-4045. doi: 10.1158/1078-0432.ccr-12-2851

Dimou, A., Non, L., Chae, Y. K., Tester, W. J. and Syrigos, K. N. (2014). MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis. PLoS One, 9(9), e107677. doi: 10.1371/journal.pone.0107677

Drilon, A., Wang, L., Arcila, M. E., Balasubramanian, S., Greenbowe, J. R., Ross, J. S., Stephens, P., Lipson, D., Miller, V. A., Kris, M. G., Ladanyi, M. and Rizvi, N. A. (2015). Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches. Clin Cancer Res. doi: 10.1158/1078-0432.ccr-14-2683

European Medicines Agency. (2015). European Medicines Agency - European public assessment reports. Retrieved 06/28, 2015, from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125&searchTab=&currentCategory=Carcinoma,%20Non-Small-Cell%20Lung&keyword=Enter%20keywords&searchType=name&alreadyLoaded=true&status=Authorised&status=W

Falchook, G., Janku, F., Tsao, A., Bastida, C., Stewart, D. and Kurzrock, R. (2013). Non-Small Cell Lung Cancer with HER2 Exon 20 Mutation: Regression with Dual HER2 Inhibition and Anti-VEGF Combination Treatment. J Thorac Oncol, 8(2), e19-20. doi: 10.1097/JTO.0b013e31827ce38e

Fan, L., Feng, Y., Wan, H., Shi, G. and Niu, W. (2014). Clinicopathological and demographical characteristics of non-small cell lung cancer patients with ALK rearrangements: a systematic review and meta-analysis. PLoS One, 9(6), e100866. doi: 10.1371/journal.pone.0100866

Ferlay, J., Steliarova-Foucher, E., Lortet-Tieulent, J., Rosso, S., Coebergh, J. W. W., Comber, H., Forman, D. and Bray, F. (2013). Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. European Journal of Cancer, 49(6), 1374-1403. doi: 10.1016/j.ejca.2012.12.027

Finberg, K. E., Sequist, L. V., Joshi, V. A., Muzikansky, A., Miller, J. M., Han, M., Beheshti, J., Chirieac, L. R., Mark, E. J. and Iafrate, A. J. (2007). Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn, 9(3), 320-326. doi: 10.2353/jmoldx.2007.060182

Gabelli, S. B., Echeverria, I., Alexander, M., Duong-Ly, K. C., Chaves-Moreira, D., Brower, E. T., Vogelstein, B. and Amzel, L. M. (2014). Activation of PI3Kalpha by physiological effectors and by oncogenic mutations: structural and dynamic effects. Biophys Rev, 6(1), 89-95. doi: 10.1007/s12551-013-0131-1

Gautschi, O., Pauli, C., Strobel, K., Hirschmann, A., Printzen, G., Aebi, S. and Diebold, J. (2012). A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol, 7(10), e23-24. doi: 10.1097/JTO.0b013e3182629903

Gibson, G. J., Loddenkemper, R., Sibille, Y. and Lundbäck, B. (2013). The European Lung White Book. Sheffield: European Respiratory Society.

Guo, B., Cen, H., Tan, X., Liu, W. and Ke, Q. (2014). Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures. PLoS One, 9(6), e99399. doi: 10.1371/journal.pone.0099399

Heavey, S., O'Byrne, K. J. and Gately, K. (2014). Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC. Cancer Treat Rev, 40(3), 445-456. doi: 10.1016/j.ctrv.2013.08.006

Hirsch, F. R., Varella-Garcia, M., Bunn, P. A., Jr., Franklin, W. A., Dziadziuszko, R., Thatcher, N., Chang, A., Parikh, P., Pereira, J. R., Ciuleanu, T., von Pawel, J., Watkins, C., Flannery, A., Ellison, G., Donald, E., Knight, L., Parums, D., Botwood, N. and Holloway, B. (2006). Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol, 24(31), 5034-5042. doi: 10.1200/jco.2006.06.3958

Howlader, N., Noone, A., Krapcho, M., Garshell, J., Miller, D., Altekruse, S., Kosary, C., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D., Chen, H., Feuer, E. and Cronin, K. (2015). SEER Cancer Statistics Review, 1975-2012. Retrieved 07/08, 2015, from http://seer.cancer.gov/csr/1975_2012/

Iragavarapu, C., Mustafa, M., Akinleye, A., Furqan, M., Mittal, V., Cang, S. and Liu, D. (2015). Novel ALK inhibitors in clinical use and development. J Hematol Oncol, 8(1), 17. doi: 10.1186/s13045-015-0122-8

Janne, P. A., Shaw, A. T., Pereira, J. R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F. A., Grinsted, L., Zazulina, V., Smith, P., Smith, I. and Crino, L. (2013). Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol, 14(1), 38-47. doi: 10.1016/s1470-2045(12)70489-8

Kang, S., Bader, A. G. and Vogt, P. K. (2005). Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A, 102(3), 802-807. doi: 10.1073/pnas.0408864102

Kong-Beltran, M., Seshagiri, S., Zha, J., Zhu, W., Bhawe, K., Mendoza, N., Holcomb, T., Pujara, K., Stinson, J., Fu, L., Severin, C., Rangell, L., Schwall, R., Amler, L., Wickramasinghe, D. and Yauch, R. (2006). Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res, 66(1), 283-289. doi: 10.1158/0008-5472.can-05-2749

Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, T. and Mitsudomi, T. (2004). Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res, 64(24), 8919-8923. doi: 10.1158/0008-5472.can-04-2818

Kwak, E. L., Bang, Y. J., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. H., Dezube, B. J., Janne, P. A., Costa, D. B., Varella-Garcia, M., Kim, W. H., Lynch, T. J., Fidias, P., Stubbs, H., Engelman, J. A., Sequist, L. V., Tan, W., Gandhi, L., Mino-Kenudson, M., Wei, G. C., Shreeve, S. M., Ratain, M. J., Settleman, J., Christensen, J. G., Haber, D. A., Wilner, K., Salgia, R., Shapiro, G. I., Clark, J. W. and Iafrate, A. J. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 363(18), 1693-1703. doi: 10.1056/NEJMoa1006448

Levy, B., Spira, A., Becker, D., Evans, T., Schnadig, I., Camidge, D. R., Bauman, J. E., Hausman, D., Walker, L., Nemunaitis, J., Rudin, C. M., Halmos, B. and Bowles, D. W. (2014). A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer. J Thorac Oncol, 9(7), 1031-1035. doi: 10.1097/jto.0000000000000183

Li, C., Sun, Y., Fang, R., Han, X., Luo, X., Wang, R., Pan, Y., Hu, H., Zhang, Y., Pao, W., Shen, L., Ji, H. and Chen, H. (2012). Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains. J Thorac Oncol, 7(1), 85-89. doi: 10.1097/JTO.0b013e318234f0a2

Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Goetzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J. and Moher, D. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med., 151(4), W65-94.

Litvak, A. M., Paik, P. K., Woo, K. M., Sima, C. S., Hellmann, M. D., Arcila, M. E., Ladanyi, M., Rudin, C. M., Kris, M. G. and Riely, G. J. (2014). Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol, 9(11), 1669-1674. doi: 10.1097/jto.0000000000000344

Luk, P. P., Yu, B., Ng, C. C., Mercorella, B., Selinger, C., Lum, T., Kao, S., O'Toole, S. A. and Cooper, W. A. (2015). BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res, 4(2), 142-148. doi: 10.3978/j.issn.2218-6751.2014.08.08

Lutterbach, B., Zeng, Q., Davis, L. J., Hatch, H., Hang, G., Kohl, N. E., Gibbs, J. B. and Pan, B. S. (2007). Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res, 67(5), 2081-2088. doi: 10.1158/0008-5472.can-06-3495

Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J. and Haber, D. A. (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. doi: 10.1056/NEJMoa040938

Manegold, C. and Thatcher, N. (2012). Cetuximab in non-small cell lung cancer. Hot Topics in Oncology, 6(9), 17-29.

Mano, H. (2008). Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci, 99(12), 2349-2355. doi: 10.1111/j.1349-7006.2008.00972.x

Marchetti, A., Felicioni, L., Malatesta, S., Grazia Sciarrotta, M., Guetti, L., Chella, A., Viola, P., Pullara, C., Mucilli, F. and Buttitta, F. (2011). Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol, 29(26), 3574-3579. doi: 10.1200/jco.2011.35.9638

Mascaux, C., Iannino, N., Martin, B., Paesmans, M., Berghmans, T., Dusart, M., Haller, A., Lothaire, P., Meert, A. P., Noel, S., Lafitte, J. J. and Sculier, J. P. (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. doi: 10.1038/sj.bjc.6602258

Mazieres, J., Peters, S., Lepage, B., Cortot, A. B., Barlesi, F., Beau-Faller, M., Besse, B., Blons, H., Mansuet-Lupo, A., Urban, T., Moro-Sibilot, D., Dansin, E., Chouaid, C., Wislez, M., Diebold, J., Felip, E., Rouquette, I., Milia, J. D. and Gautschi, O. (2013). Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol, 31(16), 1997-2003. doi: 10.1200/jco.2012.45.6095

Melosky, B. (2014). Review of EGFR TKIs in Metastatic NSCLC, Including Ongoing Trials. Front Oncol, 4, 244. doi: 10.3389/fonc.2014.00244

Ohashi, K., Sequist, L. V., Arcila, M. E., Lovly, C. M., Chen, X., Rudin, C. M., Moran, T., Camidge, D. R., Vnencak-Jones, C. L., Berry, L., Pan, Y., Sasaki, H., Engelman, J. A., Garon, E. B., Dubinett, S. M., Franklin, W. A., Riely, G. J., Sos, M. L., Kris, M. G., Dias-Santagata, D., Ladanyi, M., Bunn, P. A., Jr. and Pao, W. (2013). Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res, 19(9), 2584-2591. doi: 10.1158/1078-0432.ccr-12-3173

Onozato, R., Kosaka, T., Kuwano, H., Sekido, Y., Yatabe, Y. and Mitsudomi, T. (2009). Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol, 4(1), 5-11. doi: 10.1097/JTO.0b013e3181913e0e

Paik, J. H., Choi, C. M., Kim, H., Jang, S. J., Choe, G., Kim, D. K., Kim, H. J., Yoon, H., Lee, C. T., Jheon, S., Choe, J. Y. and Chung, J. H. (2012). Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer, 76(3), 403-409. doi: 10.1016/j.lungcan.2011.11.008

Paik, P. K., Arcila, M. E., Fara, M., Sima, C. S., Miller, V. A., Kris, M. G., Ladanyi, M. and Riely, G. J. (2011). Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol, 29(15), 2046-2051. doi: 10.1200/jco.2010.33.1280

Peters, S., Michielin, O. and Zimmermann, S. (2013). Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol, 31(20), e341-344. doi: 10.1200/jco.2012.47.6143

Peters, S. and Zimmermann, S. (2014). Targeted therapy in NSCLC driven by HER2 insertions. Transl Lung Cancer Res, 3(2), 84-88. doi: 10.3978/j.issn.2218-6751.2014.02.06

Qian, H., Gao, F., Wang, H. and Ma, F. (2014). The efficacy and safety of crizotinib in the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: a meta-analysis of clinical trials. BMC Cancer, 14, 683. doi: 10.1186/1471-2407-14-683

Rodenhuis, S. and Slebos, R. J. (1990). The ras oncogenes in human lung cancer. Am Rev Respir Dis, 142(6 Pt 2), S27-30. doi: 10.1164/ajrccm/142.6_Pt_2.S27

Rothschild, S. I. (2015). Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK. Cancers (Basel), 7(2), 930-949. doi: 10.3390/cancers7020816

Sadiq, A. A. and Salgia, R. (2013). MET as a possible target for non-small-cell lung cancer. J Clin Oncol, 31(8), 1089-1096. doi: 10.1200/jco.2012.43.9422

Samuels, Y. and Velculescu, V. E. (2004). Oncogenic mutations of PIK3CA in human cancers. Cell Cycle, 3(10), 1221-1224.

Sanchez-Torres, J. M., Viteri, S., Molina, M. A. and Rosell, R. (2013). BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors. Transl Lung Cancer Res, 2(3), 244-250. doi: 10.3978/j.issn.2218-6751.2013.04.01

Scheffler, M., Bos, M., Gardizi, M., Konig, K., Michels, S., Fassunke, J., Heydt, C., Kunstlinger, H., Ihle, M., Ueckeroth, F., Albus, K., Serke, M., Gerigk, U., Schulte, W., Topelt, K., Nogova, L., Zander, T., Engel-Riedel, W., Stoelben, E., Ko, Y. D., Randerath, W., Kaminsky, B., Panse, J., Becker, C., Hellmich, M., Merkelbach-Bruse, S., Heukamp, L. C., Buttner, R. and Wolf, J. (2015). PIK3CA mutations in non-small cell lung cancer (NSCLC): genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget, 6(2), 1315-1326.

Scheffler, M., Schultheis, A., Teixido, C., Michels, S., Morales-Espinosa, D., Viteri, S., Hartmann, W., Merkelbach-Bruse, S., Fischer, R., Schildhaus, H. U., Fassunke, J., Sebastian, M., Serke, M., Kaminsky, B., Randerath, W., Gerigk, U., Ko, Y. D., Kruger, S., Schnell, R., Rothe, A., Kropf-Sanchen, C., Heukamp, L., Rosell, R., Buttner, R. and Wolf, J. (2015). ROS1 rearrangements in lung adenocarcinoma: prognostic impact, therapeutic options and genetic variability. Oncotarget, 6(12), 10577-10585.

Schildhaus, H. U., Schultheis, A. M., Ruschoff, J., Binot, E., Merkelbach-Bruse, S., Fassunke, J., Schulte, W., Ko, Y. D., Schlesinger, A., Bos, M., Gardizi, M., Engel-Riedel, W., Brockmann, M., Serke, M., Gerigk, U., Hekmat, K., Frank, K. F., Reiser, M., Schulz, H., Kruger, S., Stoelben, E., Zander, T., Wolf, J. and Buettner, R. (2015). MET amplification status in therapy-naive adeno- and squamous cell carcinomas of the lung. Clin Cancer Res, 21(4), 907-915. doi: 10.1158/1078-0432.ccr-14-0450

Shaw, A. T., Ou, S. H., Bang, Y. J., Camidge, D. R., Solomon, B. J., Salgia, R., Riely, G. J., Varella-Garcia, M., Shapiro, G. I., Costa, D. B., Doebele, R. C., Le, L. P., Zheng, Z., Tan, W., Stephenson, P., Shreeve, S. M., Tye, L. M., Christensen, J. G., Wilner, K. D., Clark, J. W. and Iafrate, A. J. (2014). Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med, 371(21), 1963-1971. doi: 10.1056/NEJMoa1406766

Shaw, A. T., Yeap, B. Y., Mino-Kenudson, M., Digumarthy, S. R., Costa, D. B., Heist, R. S., Solomon, B., Stubbs, H., Admane, S., McDermott, U., Settleman, J., Kobayashi, S., Mark, E. J., Rodig, S. J., Chirieac, L. R., Kwak, E. L., Lynch, T. J. and Iafrate, A. J. (2009). Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol, 27(26), 4247-4253. doi: 10.1200/jco.2009.22.6993

Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, II, Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., Fujisawa, T., Feng, Z., Roth, J. A., Herz, J., Minna, J. D. and Gazdar, A. F. (2005). Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst, 97(5), 339-346. doi: 10.1093/jnci/dji055

Shigematsu, H., Takahashi, T., Nomura, M., Majmudar, K., Suzuki, M., Lee, H., Wistuba, II, Fong, K. M., Toyooka, S., Shimizu, N., Fujisawa, T., Minna, J. D. and Gazdar, A. F. (2005). Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res, 65(5), 1642-1646. doi: 10.1158/0008-5472.can-04-4235

Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S., Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y. and Mano, H. (2007). Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 448(7153), 561-566. doi: 10.1038/nature05945

Spigel, D. R., Ervin, T. J., Ramlau, R. A., Daniel, D. B., Goldschmidt, J. H., Jr., Blumenschein, G. R., Jr., Krzakowski, M. J., Robinet, G., Godbert, B., Barlesi, F., Govindan, R., Patel, T., Orlov, S. V., Wertheim, M. S., Yu, W., Zha, J., Yauch, R. L., Patel, P. H., Phan, S. C. and Peterson, A. C. (2013). Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol, 31(32), 4105-4114. doi: 10.1200/jco.2012.47.4189

Suzuki, M., Shiraishi, K., Yoshida, A., Shimada, Y., Suzuki, K., Asamura, H., Furuta, K., Kohno, T. and Tsuta, K. (2015). HER2 gene mutations in non-small cell lung carcinomas: concurrence with Her2 gene amplification and Her2 protein expression and phosphorylation. Lung Cancer, 87(1), 14-22. doi: 10.1016/j.lungcan.2014.10.014

Takeda, M., Okamoto, I., Sakai, K., Kawakami, H., Nishio, K. and Nakagawa, K. (2012). Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy. Ann Oncol, 23(11), 2931-2936. doi: 10.1093/annonc/mds124

Telesco, S. E., Shih, A., Liu, Y. and Radhakrishnan, R. (2011). Investigating Molecular Mechanisms of Activation and Mutation of the HER2 Receptor Tyrosine Kinase through Computational Modeling and Simulation. Cancer Res J, 4(4), 1-35.

Tomizawa, K., Suda, K., Onozato, R., Kosaka, T., Endoh, H., Sekido, Y., Shigematsu, H., Kuwano, H., Yatabe, Y. and Mitsudomi, T. (2011). Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer, 74(1), 139-144. doi: 10.1016/j.lungcan.2011.01.014

Tong, L. A., de Vos, A. M., Milburn, M. V., Jancarik, J., Noguchi, S., Nishimura, S., Miura, K., Ohtsuka, E. and Kim, S. H. (1989). Structural differences between a ras oncogene protein and the normal protein. Nature, 337(6202), 90-93. doi: 10.1038/337090a0

Travis, W. D., Brambilla, E., Noguchi, M., Nicholson, A. G., Geisinger, K. R., Yatabe, Y., Beer, D. G., Powell, C. A., Riely, G. J., Van Schil, P. E., Garg, K., Austin, J. H., Asamura, H., Rusch, V. W., Hirsch, F. R., Scagliotti, G., Mitsudomi, T., Huber, R. M., Ishikawa, Y., Jett, J., Sanchez-Cespedes, M., Sculier, J. P., Takahashi, T., Tsuboi, M., Vansteenkiste, J., Wistuba, I., Yang, P. C., Aberle, D., Brambilla, C., Flieder, D., Franklin, W., Gazdar, A., Gould, M., Hasleton, P., Henderson, D., Johnson, B., Johnson, D., Kerr, K., Kuriyama, K., Lee, J. S., Miller, V. A., Petersen, I., Roggli, V., Rosell, R., Saijo, N., Thunnissen, E., Tsao, M. and Yankelewitz, D. (2011). International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 6(2), 244-285. doi: 10.1097/JTO.0b013e318206a221

Villaruz, L. C., Socinski, M. A., Abberbock, S., Berry, L. D., Johnson, B. E., Kwiatkowski, D. J., Iafrate, A. J., Varella-Garcia, M., Franklin, W. A., Camidge, D. R., Sequist, L. V., Haura, E. B., Ladanyi, M., Kurland, B. F., Kugler, K., Minna, J. D., Bunn, P. A. and Kris, M. G. (2015). Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer, 121(3), 448-456. doi: 10.1002/cncr.29042

Vujic, I., Posch, C., Sanlorenzo, M., Yen, A. J., Tsumura, A., Kwong, A., Feichtenschlager, V., Lai, K., Arneson, D. V., Rappersberger, K. and Ortiz-Urda, S. M. (2014). Mutant NRASQ61 shares signaling similarities across various cancer types--potential implications for future therapies. Oncotarget, 5(17), 7936-7944.

Vujic, I., Sanlorenzo, M., Posch, C., Esteve-Puig, R., Yen, A. J., Kwong, A., Tsumura, A., Murphy, R., Rappersberger, K. and Ortiz-Urda, S. (2015). Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget, 6(2), 969-978.

Wan, P. T., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M., Jones, C. M., Marshall, C. J., Springer, C. J., Barford, D. and Marais, R. (2004). Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 116(6), 855-867.

Wang, L., Hu, H., Pan, Y., Wang, R., Li, Y., Shen, L., Yu, Y., Li, H., Cai, D., Sun, Y. and Chen, H. (2014). PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PLoS One, 9(2), e88291. doi: 10.1371/journal.pone.0088291

Wang, S. E., Narasanna, A., Perez-Torres, M., Xiang, B., Wu, F. Y., Yang, S., Carpenter, G., Gazdar, A. F., Muthuswamy, S. K. and Arteaga, C. L. (2006). HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell, 10(1), 25-38. doi: 10.1016/j.ccr.2006.05.023

Weinstein, I. B. (2002). Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science, 297(5578), 63-64.

Yang, P., Kulig, K., Boland, J. M., Erickson-Johnson, M. R., Oliveira, A. M., Wampfler, J., Jatoi, A., Deschamps, C., Marks, R., Fortner, C., Stoddard, S., Nichols, F., Molina, J., Aubry, M. C., Tang, H. and Yi, E. S. (2012). Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol, 7(1), 90-97. doi: 10.1097/JTO.0b013e31823c5c32

Zhang, L., Shi, L., Zhao, X., Wang, Y. and Yue, W. (2013). PIK3CA gene mutation associated with poor prognosis of lung adenocarcinoma. Onco Targets Ther, 6, 497-502. doi: 10.2147/ott.s41643

Zhang, Q., Dai, H. H., Dong, H. Y., Sun, C. T., Yang, Z. and Han, J. Q. (2014). EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: a meta-analysis. Lung Cancer, 85(3), 339-345. doi: 10.1016/j.lungcan.2014.06.011

Zhang, W. Q., Li, T. and Li, H. (2014). Efficacy of EGFR tyrosine kinase inhibitors in non-small-cell lung cancer patients with/without EGFR-mutation: evidence based on recent phase III randomized trials. Med Sci Monit, 20, 2666-2676. doi: 10.12659/msm.892476

Zhang, Z., Wang, T., Zhang, J., Cai, X., Pan, C., Long, Y., Chen, J., Zhou, C. and Yin, X. (2014). Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis. PLoS One, 9(8), e106053. doi: 10.1371/journal.pone.0106053

Zhu, Q., Zhan, P., Zhang, X., Lv, T. and Song, Y. (2015). Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res, 4(3), 300-309. doi: 10.3978/j.issn.2218-6751.2015.05.01

DOI: http://dx.doi.org/10.18103/mra.v2i6.411


  • There are currently no refbacks.