Figures and Tables

Supplementary Table Section

Table legends

Table 1: Anti-EGFR drugs that are approved for cancer treatment.

Table 2: Cells used for recombinant expression of EGFR variants. Summary of cellular models transiently (t) or stably (s) transfected with EGFR variants.

Table 3: NSCLC cells with endogenous EGFR mutations and wildtype EGFR. Summary of lung cancer cell lines with endogenous EGFR kinase domain mutations and wildtype EGFR. 1 Cell lines available at ATCC. 2 Cell lines that have been successfully transfected according to published literature.

Table 4: Summary on clinical examination conducted in the context of EGFR kinase domain mutations in NSCLC patients. Adapted from Sequist et al. (Sequist et al., 2005) and updated; “---“ indicates that data were not explicitly reported in the cited articles. Some of the numbers were calculated from published primary data. 1 Response as defined in the cited articles. 2 Only Japanese patients (n=10) included in calculation of median survival. 3 Includes silent mutations. 4 All stable disease. 5 These data comprise only a part of the total data from IDEAL and INTACT trials. 6 not reached (NR) at time of publication.

Table 5: Prevalence of EGFR kinase domain mutations in NSCLC patients and their correlation with other molecular events. The right column (*) depicts selected factors that may be deregulated or mutated in lung cancer, but have not yet been extensively analyzed in context with EGFR kinase domain mutations. Tables

Table 1: Anti-EGFR drugs that are approved for cancer treatment.

Drug Company Compound Class Indications Gefitinib Astra Zeneca TKI NSCLC after failure (ZD1839/ Iressa) of standard treatments (de Bono and Rowinsky, 2002; Laskin and Sandler, 2004) Erlotinib OSI TKI NSCLC after failure (CP-358,774/ Pharmaceuticals/ of standard Genentech/ Roche treatments Tarceva/ OSI-774) (de Bono and Rowinsky, 2002; Laskin and Sandler, 2004) Cetuximab ImClone Systems/ Chimeric anti-EGFR Advanced colon (C225/ Erbitux) Bristol-Myers monoclonal antibody rectal cancer (CRC) Squibb/ Merck and squamous cell (Janmaat and Giaccone, KGaA carcinoma of the 2003; Harding and Burtness, 2005) head and neck (SCCHN) Nimotuzumab YM BioSciences/ Humanized anti- SCCHN (in India, (TheraCim/ hR-3) Oncoscience/ EGFR monoclonal Argentina, Columbia CIMAB SA/ Biocon antibody and Cuba), (Spicer et al., 2005) Biopharmaceuticals nasopharyngeal cancer (in China) Panitumumab Abgenix/ Amgen Fully human anti- Chemotherapy- (ABX-EGF/ Vectibix) EGFR monoclonal resistant CRC antibody (Davis et al., 1999; Cohenuram and Saif, 2007) Table 2: Cells used for recombinant expression of EGFR variants.

Cell line Tissue Transient (t)/ Stable (s) transfection Cos-7 African green monkey, kidney t (Lynch et al., 2004a), t (Sordella et al., 2004), t (Choong et al., 2006) NIH-3T3 Murine fibroblasts s (Greulich et al., 2005), t (Greulich et al., 2005), s (Mukohara et al., 2005), s (Shimamura et al., 2005), s (Alvarez et al., 2006), HEK293T Human kidney s (Arao et al., 2004), t (Pao et al., 2004), t (Amann et al., 2005), s (Sakai et al., 2006), NMuMg Murine mammary epithelium s (Sordella et al., 2004) CHO Chinese hamster ovary s (Amann et al., 2005), t (Engelman et al., 2005) H1299 Human NSCLC s (Chen et al., 2006) 32D Murine IL-3 dependent myeloid s (Chen et al., 2006) cells Hela Human cervix tumor t (Greulich et al., 2005) hTBE Human tracheobronchial s (Greulich et al., 2005) epithelium Baf/F3 Murine IL-3 dependent proB s (Jiang et al., 2005) lymphoid cells NR6 Murine fibroblasts s (Carey et al., 2006) PC-13 Human lung large cell carcinoma t (Akca et al., 2006) Table 3: NSCLC cells with endogenous EGFR mutations and wildtype EGFR.

Cell line EGFR Other characteristics H3255 L858R, EGFR amplification high ErbB2, ErbB3 and epiregulin expression (Tracy, 2004; Amann et al., 2005; Engelman et al., 2005; detectable amphiregulin Haura et al., 2005; Paez et al., 2004; Mukohara et al., 2005; no secretion of TGF Shimamura et al., 2005; Alvarez, 2006; Engelman, 2006) H1650 [1] delE746-A750 lack of PTEN (Sordella et al., 2004; Kwak et al., 2005; Shimamura et al., wildtype K-RAS 2005; Janmaat et al., 2006; Haura et al., 2005) H1975 [1] L858R + T790M wildtype K-RAS (Sordella et al., 2004; Haura et al., 2005; Kwak et al., 2005; Pao et al., 2005a; Shimamura et al., 2005; Yauch et al., 2005; Engelman et al., 2006) HCC-827 [1] delE746-A750, amplification high ErbB3, epiregulin and amphiregulin expression (Amann et al., 2005; Fujimoto, et al., 2005; Mukohara et al., detectable ErbB2 2005; Alvarez et al., 2006, Engelmann et al., 2006) HCC2279 del746-750; high expression detectable epiregulin and amphiregulin (Fujimoto et al., 2005; Coldren et al., 2006) of EGFR low Akt expression no ErbB2 and ErbB3 wildtype K-RAS H4006 del746-750, S752V; detectable ErbB3, epiregulin and amphiregulin (Fujimoto et al., 2005; Coldren et al., 2006) medium EGFR expression ErbB2 expression low wildtype K-RAS PC-9 [2] delE746-A750, also express high ErbB3 expression (Kakiuchi et al., 2004; Ono et al., 2004; Tracy et al., 2004; some wildtype EGFR medium EGF and TGF expression Mukohara et al., 2005; Akca et al., 2006; Sakai et al., 2006) low ErbB2 and ErbB4 expression DFCILU-011 delL747-E749 high ErbB3 expression (Engelman et al., 2005; Mukohara et al., 2005) H820 [2] Non-specified deletion contradicting K-RAS mutation data (Coldren, 2006; (Coldren et al., 2006) mutation Okudela, 2004) H1781 [1,2] Wildtype ErbB2-G776V mutation (Paez et al., 2004; Yauch et al., 2005) wildtype K-RAS H1666 [1] Wildtype TGF secretion Paez et al., 2004; Tracy et al., 2004; Sordella et al., 2004; wildtype K-RAS Mukohara et al., 2005; Shimamura et al., 2005) H358 [1,2] Wildtype high ErbB3 expression (Kakiuchi et al., 2004; Sordella et al., 2004; Engelman et al., detectable ErbB2 and amphiregulin 2005; Haura et al., 2005; Pao et al., 2005a) no ErbB4 expression K-RAS mutation H1734 [1,2] Wildtype K-RAS mutation (Sordella, 2004; Pao et al., 2005a) H1819 [1] Wildtype, small increase in ErbB2 amplification (Amann et al., 2005; Fujimoto et al., 2005) copy number high ErbB3 expression detectable amphiregulin and epiregulin H1299 [1,2] Wildtype, small increase in medium TGF expression (Lee et al., 2003; Amann et al., 2005; Engelman et al., copy number low ErbB3 expression 2005; Haura et al., 2005; Yauch et al., 2005, Akca et al., no ErbB2 and ErbB4 expression 2006) p53 mutation, wildtype PTEN and K-RAS A549 [1,2] Wildtype high TGF expression (Tracy et al., 2004; Amann et al., 2005; Engelmann et al., low ErbB2 and ErbB3 expression 2005; Haura et al., 2005; Mukohara et al., 2005; Shimamura detectable PTEN et al., 2005; Yauch et al., 2005) no EGF expression K-RAS mutation H441 [1,2] Wildtype ErbB2 and ErbB3 constitutively active (Paez et al., 2004; Mukohara et al., 2005; Yauch et al., detectable TGF secretion 2005) K-RAS and p53 mutation lack of PTEN H23 [1,2] Wildtype no ErbB2 and ErbB3 expression (Engelman et al., 2005; Yauch et al., 2005) p53 and K-RAS mutation H292 [1,2] Wildtype, high expression medium ErbB3 and EGF expression (Janmaat et al., 2006) detectable PTEN low ErbB2, HB-EGF and TGF expression K-RAS wildtype Calu-3 [1,2] Wildtype High ErbB2 and ErbB3 expression (Engelman et al., 2005) Calu-1 [1,2] Wildtype, small increase in No ErbB2 and ErbB3 expression (Amann et al., 2005; Shimamura et al., 2005; Yauch et al., copy number wildtype K-RAS 2005) H2030 [1] Wildtype K-RAS mutation (Pao et al., 2005a) Table 4: Summary on clinical examination conducted in the context of EGFR kinase domain mutations in NSCLC patients.

Authors EGFR Number Response rate Median Adenocarcinoma Female Never- status of to gefitinib or survival or BAC (%) (%) Smokers/Non- subjects erlotinib (%) 1 (months) Smokers (%) Lynch et al., Mut 8 100 --- 100 63 63 2004a Wt 8 13 ------Paez et al., Mut 5 100 --- 100 60 --- 2004 Wt 4 0 --- 75 75 --- Pao et al., Mut 17 100 ------2004 Wt 43 12 ------Pao, 2005b Mut 22 77 ------Wt 38 13 ------Huang et al., Mut 8 78 --- 100 75 88 2004 Wt 8 14 --- 13 75 63 Tokumo et Mut 9 89 25 89 56 78 al., 2005 Wt 12 17 14 58 25 0 Mitsudomi et Mut 33 83 NR 6 97 58 61 al., 2005 Wt 26 10 ~17 31 31 31 Han et al., Mut 17 65 31 82 71 65 2005 Wt 73 14 7 ------Taron et al., Mut 17 94 NR 6 100 65 82 2005 Wt 51 12 10 59 24 16 Kondo et al., Mut 4 100 --- 100 50 75 2005 Wt 8 0 --- 63 50 25 Rosell et al., Mut 8 88 16 2 100 50 62 2005 Wt 24 13 2 2 77 27 20 Tomizawa et Mut 10 100 --- 100 60 60 (n) al., 2005 Wt 10 3 40 --- 80 50 50 (n) Zhang et al., Mut 12 67 NR 6 92 75 91 (n) 2005 Wt 18 6 7 56 28 39 (n) Tsao et al., Mut 19 16 ------2005 Wt 81 7 ------Takano et al., Mut 39 82 20 97 46 54 2005 Wt 27 11 7 89 39 37 Niho et al., Mut 4 100 16 100 75 25 2006 Wt 9 67 4 11 78 22 0 Kimura et al., Mut 13 54 20 85 54 --- 2006 Wt 14 14 8 86 21 --- Kim et al., Mut 6 100 16 83 50 67 2005 Wt 21 --- 5 ------Cortes- Mut 10 60 13 100 70 60 Funes et al., Wt 72 8 5 44 25 20 2005 Cappuzzo et Mut 15 53 21 80 53 40 al., 2005a Wt 74 5 8 62 31 9 Chou et al., Mut 33 52 15 88 55 76 2005 Wt 21 19 5 --- Uramoto et Mut 9 78 13 100 44 56 al., 2006 Wt 11 0 4 72 45 27 Bell et al., Mut 13 5 46 5 --- 80 50 39 2005a Wt 56 5 9 5 --- 51 29 14 Mu et al., Mut 10 100 --- 90 70 --- 2005 Wt 12 3 33 --- 64 45 --- Ishikawa et Mut 6 50 --- 83 50 67 al., 2005 Wt 7 14 --- 50 25 38 Shih et al., Mut 29 69 --- 96 79 79 2006 Wt 33 9 --- 88 45 55 Table 5: Prevalence of EGFR kinase domain mutations in NSCLC patients and their correlation with other molecular events.

Positive Negative No Unclear Correlation Correlation Correlation Correlation (*) Increased genomic Increased methylation EGFR Mutation of B-Raf (v- EGFR copy number of SPARC (secreted overexpression raf murine sarcoma (Taron et al., 2005; protein acidic and rich (Taron et al., viral oncogene Takano et al., 2005) in cysteine) promoter 2005) homolog B1) (Naoki region (Suzuki et al., et al., 2002; Brose et 2006) al., 2002); Deregulation of Ras- Raf-MAPK signaling (Adjei, 2005) Increased number of K-RAS mutation p53 mutation PI3K mutation CA repeats (Taron et (Kosaka et al., 2004; (Kondo et al., (Samuels et al., 2004; al., 2005) Pao et al., 2005b; 2005) Kawano et al., 2006) Soung et al., 2005; Shigematsu et al., 2005a; Yokoyama et al., 2006) Increased phospho- ErbB2 mutation ErbB2 c-Met (hepatocyte STAT5 levels (Haura (Stephens et al., 2004; amplification growth factor et al., 2005) Shigematsu, et al., (Endo et al., receptor) mutation 2005b; Yokoyama et 2006) (Kong-Beltran et al., al., 2006) 2006) Activation of mTOR ErbB4 mutation Deregulation of Wnt (mammalian target of (Soung et al., (wingless-type MMTV Rapamycin) 2006) integration site family) signaling (Conde et signaling (Uematsu et al., 2006) al., 2003) ErbB2 and Increased PP2a (protein concomitant EGFR phospho-Akt phosphatase 2A) gene amplification levels (Han et al., (Wang et al., 1998) (Cappuzzo et al., 2006) 2005b) EGFR Increased Neurotrophin/ overexpression phospho-MAPK neurotrophin receptor (Suzuki et al., 2005) levels (Han et al., expression (Ricci et 2006) al., 2001) Calveolin-1 EMP-1 (epithelial mRNA membrane protein 1) overexpression expression (Jain et (Taron et al., al., 2005) 2005) SOCS-3 (suppressor of cytokine signaling 3) expression (He et al., 2003) Supplementary information

Supplementary literature (cited in tables) Adjei AA (2005). Targeting multiple signal transduction pathways in lung cancer. Clin Lung Cancer 7: S39-S44.

Akca H, Tani M, Hishida T, Matsumoto S, Yokota J (2006). Activation of the AKT and STAT3 pathways and prolonged survival by a mutant EGFR in human lung cancer cells. Lung Cancer 54: 25-33.

Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA (2006). STAT3 is required for the oncogenic effects of NSCLC-associated mutations of the EGFR. Cancer Res 66: 3162-3168.

Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R et al. (2002). BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62: 6997-7000.

Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL et al. (2005b). Increased HER2 gene copy number is associated with response to gefitinib therapy in EGFR-positive NSCLC patients. J Clin Oncol 23: 5007-5018.

Chou TY, Chiu CH, Li LH, Hsiao CY, Tzen CY, Chang KT et al. (2005). Mutation in the tyrosine kinase domain of EGFR is a predictive and prognostic factor for gefitinib treatment in patients with NSCLC. Clin Cancer Res 11: 3750-3757.

Cohenuram M, Saif MW (2007). Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. Anticancer Drugs 18: 7-15.

Conde E, Angulo B, Tang M, Morente M, Torres-Lanzas J, Lopez-Encuentra A et al. (2006). Molecular context of the EGFR mutations: evidence for the activation of mTOR/S6K signaling. Clin Cancer Res 12: 710-717.

Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C, Velasco A et al. (2005). EGFR activating mutations in Spanish gefitinib-treated NSCLC patients. Ann Oncol 16: 1081-1086.

Davis CG, Gallo ML, Corvalan JR (1999). Transgenic mice as a source of fully human antibodies for the treatment of cancer. Cancer Metastasis Rev 18: 421-425.

De Bono JS, Rowinsky EK (2002). The ErbB receptor family: a therapeutic target for cancer. Trends Mol Med 8: S19-S26.

Endo K, Sasaki H, Yano M, Kobayashi Y, Yukiue H, Haneda H et al. (2006). Evaluation of the EGFR gene mutation and copy number in NSCLC with gefitinib therapy. Oncol Rep 16: 533-541. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS et al. (2005). Predictive and prognostic impact of EGFR mutation in NSCLC patients treated with gefitinib. J Clin Oncol 23: 2493-2501.

Han SW, Kim TY, Jeon YK, Hwang PG, Im SA, Lee KH et al. (2006). Optimization of patient selection for gefitinib in NSCLC by combined analysis of EGFR mutation, K- Ras mutation, and Akt phosphorylation. Clin Cancer Res 12: 2538-2544.

Harding J, Burtness B (2005). Cetuximab: an EGFR chemeric human-murine monoclonal antibody. Drugs Today (Barc.) 41: 107-127.

Haura EB, Zheng Z, Song L, Cantor A, Bepler G (2005). Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res 11: 8288-8294.

He B, You L, Uematsu K, Zang K, Xu Z, Lee AY et al. (2003). SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100: 14133-14138.

Huang SF, Liu HP, Li LH, Ku YC, Fu YN, Tsai HY et al. (2004). High frequency of EGFR mutations with complex patterns in NSCLC related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10: 8195-8203.

Ishikawa N, Daigo Y, Takano A, Taniwaki M, Kato T, Hayama S et al. (2005). Increases of amphiregulin and TGF in serum as predictors of poor response to gefitinib among patients with advanced NSCLC. Cancer Res 65: 9176-9184.

Janmaat ML, Giaccone G (2003). The EGFR pathway and its inhibition as anticancer therapy. Drugs Today (Barc.) 39 Suppl C: 61-80.

Jain A, Tindell CA, Laux I, Hunter JB, Curran J, Galkin A et al. (2005). Epithelial membrane protein-1 is a biomarker of gefitinib resistance. Proc Natl Acad Sci USA 102: 11858-11863.

Kakiuchi S, Daigo Y, Ishikawa N, Furukawa C, Tsunoda T, Yano S et al. (2004). Prediction of sensitivity of advanced NSCLC to gefitinib. Hum Mol Genet 13: 3029- 3043.

Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H et al. (2006). PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54: 209-215. Kim KS, Jeong JY, Kim YC, Na KJ, Kim YH, Ahn SJ et al. (2005) Predictors of the response to gefitinib in refractory NSCLC. Clin Cancer Res 11: 2244-2251.

Kondo M, Yokoyama T, Fukui T, Yoshioka H, Yokoi K, Nagasaka T et al. (2005). Mutations of EGFR of NSCLC were associated with sensitivity to gefitinib in recurrence after surgery. Lung Cancer 50: 385-391.

Kong-Beltran M, Seshagiri S, Zha J, Zhu W, Bhawe K, Mendoza N et al. (2006). Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res 66: 283-289.

Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T (2004). Mutations of the EGFR gene in lung cancer: biological and clinical implications. Cancer Res 64: 8919-8923.

Laskin JJ, Sandler AB (2004). EGFR: a promising target in solid tumours. Cancer Treat Rev 30: 1-17.

Lee HY, Srinivas H, Xia D, Lu Y, Superty R, LaPushin R et al. (2003). Evidence that PI3K- and MAPKK-4/JNK-dependent Pathways cooperate to maintain lung cancer cell survival. J Biol Chem 278: 23630-23638.

Mu XL, Li LY, Zhang XT, Wang MZ, Feng RE, Cui QC et al. (2005). Gefitinib- sensitive mutations of the EGFR tyrosine kinase domain in chinese patients with NSCLC. Clin Cancer Res 11: 4289-4294.

Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M (2002). Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 62: 7001- 7003.

Ono M, Hirata A, Kometani T, Miyagawa M, Ueda S, Kinoshita H et al. (2004). Sensitivity to gefitinib (Iressa, ZD1839) in NSCLC cell lines correlates with dependence on the EGFR/ERK1/2 and EGFR/Akt pathway for proliferation. Mol Cancer Ther 3: 465-472.

Ricci A, Greco S, Mariotta S, Felici L, Bronzetti E, Cavazzana A et al. (2001). Neurotrophins and neurotrophin receptors in human lung cancer. Am J Respir Cell Mol Biol 25: 439-446. Rosell R, Ichinose Y, Taron M, Sarries C, Queralt C, Mendez P et al. (2005). Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in NSCLC. Lung Cancer 50: 25-33.

Sakai K, Arao T, Shimoyama T, Murofushi K, Sekijima M, Kaji N et al. (2006). Dimerization and the signal transduction pathway of a small in-frame deletion in the EGFR. FASEB J 20: 311-313.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.

Sequist LV, Haber DA, Lynch TJ (2005). EGFR mutations in NSCLC: predicting clinical response to kinase inhibitors. Clin Cancer Res 11: 5668-5670.

Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H et al. (2005b). Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65: 1642-1646.

Shih JY, Gow CH, Yu CJ, Yang CH, Chang YL, Tsai MF et al. (2006). EGFR mutations in needle biopsy/aspiration samples predict response to gefitinib therapy and survival of patients with advanced NSCLC. Int J Cancer 118: 963-969.

Soung YH, Lee JW, Kim SY, Seo SH, Park WS, Nam SW et al. (2005). Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch 446: 483-488.

Soung YH, Lee JW, Kim SY, Wang YP, Jo K H, Moon SW et al. (2006) Somatic mutations of the ERBB4 kinase domain in human cancers. Int. J. Cancer 118: 1426- 1429.

Spicer J (2005). Technology evaluation: nimotuzumab, the Center of Molecular Immunology/YM BioSciences/Oncoscience. Curr Opin Mol Ther 7: 182-191

Suzuki M, Shigematsu H, Hiroshima K, Iizasa T, Nakatani Y, Minna JD et al. (2005). EGFR expression status in lung cancer correlates with its mutation. Hum Pathol 36: 1127-1134.

Suzuki M, Shigematsu H, Iizasa T, Hiroshima K, Nakatani Y, Minna JD et al. (2006). Exclusive mutation in EGFR gene, HER-2, and KRAS, and synchronous methylation of NSCLC. Cancer 106: 2200-2207. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J et al. (2004). Lung cancer: intragenic ErbB2 kinase mutations in tumours. Nature 431: 525-526.

Taron M, Ichinose Y, Rosell R, Mok T, Massuti B, Zamora L et al. (2005). Activating mutations in the tyrosine kinase domain of the EGFR are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 11: 5878-5885.

Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M et al. (2005). The relationship between EGFR mutations and clinicopathologic features in NSCLC. Clin Cancer Res 11: 1167-1173.

Tomizawa Y, Iijima H, Sunaga N, Sato K, Takise A, Otani Y et al. (2005). Clinicopathologic significance of the mutations of the EGFR gene in patients with NSCLC. Clin Cancer Res 11: 6816-6822.

Uematsu,K, He B, You L, Xu Z, McCormick F, Jablons DM (2003). Activation of the Wnt pathway in NSCLC: evidence of dishevelled overexpression. Oncogene 22: 7218-7221.

Uramoto H, Sugio K, Oyama T, Ono K, Sugaya M, Yoshimatsu T et al. (2006). EGFR mutations are associated with gefitinib sensitivity in NSCLC in Japanese. Lung Cancer 51: 71-77.

Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J et al. (1998). Alterations of the PPP2R1B gene in human lung and colon cancer. Science 282: 284-287.

Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L et al. (2005). Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11: 8686-8698.

Yokoyama T, Kondo M, Goto Y, Fukui T, Yoshioka H, Yokoi K et al. (2006). EGFR point mutation in NSCLC is occasionally accompanied by a second mutation or amplification. Cancer Sci 97: 753-759.

Zhang XT, Li LY, Mu XL, Cui QC, Chang XY, Song W et al. (2005). The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced NSCLC. Ann Oncol 16: 1334-1342.