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PDBsum entry 2jiu

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2jiu
Jmol
Contents
Protein chain
304 a.a. *
Ligands
AEE
Waters ×60
* Residue conservation analysis
PDB id:
2jiu
Name: Transferase
Title: Crystal structure of egfr kinase domain t790m mutation in complex with aee788
Structure: Epidermal growth factor receptor. Chain: a, b. Fragment: kinase domain, residues 695-1022. Synonym: receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes. Other_details: egfr 696-1022 t790m
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Other_details: egfr 696-1022 t790m
Resolution:
3.05Å     R-factor:   0.214     R-free:   0.277
Authors: C.-H.Yun,K.E.Mengwasser,A.V.Toms,M.S.Woo,H.Greulich, K.-K.Wong,M.Meyerson,M.J.Eck
Key ref:
C.H.Yun et al. (2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A, 105, 2070-2075. PubMed id: 18227510 DOI: 10.1073/pnas.0709662105
Date:
01-Jul-07     Release date:   22-Jan-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
304 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0709662105 Proc Natl Acad Sci U S A 105:2070-2075 (2008)
PubMed id: 18227510  
 
 
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.
C.H.Yun, K.E.Mengwasser, A.V.Toms, M.S.Woo, H.Greulich, K.K.Wong, M.Meyerson, M.J.Eck.
 
  ABSTRACT  
 
Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the "gatekeeper" residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a "generic" resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
 
  Selected figure(s)  
 
Figure 1.
Chemical structures of selected EGFR inhibitors. All compounds are drawn in a consistent orientation and conformation that reflects their approximate binding mode in the EGFR kinase. HKI-272 and EKB-569 are examples of irreversible inhibitors. Lapatinib and HKI-272 are thought to require the inactive conformation of EGFR for binding because of their additional aniline substitutions.
Figure 2.
Crystal structures of the EGFR T790M mutant show that inhibitors are readily accommodated in the active and inactive conformations of the kinase. (A) Superposition of EGFR T790M/AEE788 complex (yellow) and WT/AEE788 complex [light blue; drawn from PDB ID code 2J6M (8)]. Dashed lines indicate hydrogen bonds to the kinase hinge region that are preserved in both complexes. The location of the T790M mutation is indicated. (B) Superposition of EGFR T790M/AEE788 complex (yellow) and apo-T790M structure (green). Note the alternate side-chain conformation of Met-790 in the presence of the inhibitor. (C) Crystal structure of HKI-272 in complex with the T790M mutant. The kinase adopts an inactive conformation, with the C-helix displaced. A covalent bond is formed between Cys-797 and the crotonamide Michael acceptor of HKI-272. (D) The structure of the T790M mutant in complex with HKI-272 (yellow) is superimposed on the structure of the WT EGFR kinase in complex with Lapatinib [light blue; drawn from PDB ID code 1XKK (32)]. In both structures, the kinase adopts the same inactive conformation and the inhibitors bind in a similar manner, with a single hydrogen bond to the hinge (dashed lines) and with their aniline substituents extending into the enlarged hydrophobic pocket that is characteristic of the inactive conformation.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22473102 D.R.Camidge, and R.C.Doebele (2012).
Treating ALK-positive lung cancer--early successes and future challenges.
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22751098 Z.Zhang, J.C.Lee, L.Lin, V.Olivas, V.Au, T.LaFramboise, M.Abdel-Rahman, X.Wang, A.D.Levine, J.K.Rho, Y.J.Choi, C.M.Choi, S.W.Kim, S.J.Jang, Y.S.Park, W.S.Kim, D.H.Lee, J.S.Lee, V.A.Miller, M.Arcila, M.Ladanyi, P.Moonsamy, C.Sawyers, T.J.Boggon, P.C.Ma, C.Costa, M.Taron, R.Rosell, B.Halmos, and T.G.Bivona (2012).
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer.
  Nat Genet, 44, 852-860.  
21701501 D.C.Swinney, and J.Anthony (2011).
How were new medicines discovered?
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21320004 D.S.Subramaniam, and J.Hwang (2011).
BIBW 2992 in non-small cell lung cancer.
  Expert Opin Investig Drugs, 20, 415-422.  
21455239 J.Singh, R.C.Petter, T.A.Baillie, and A.Whitty (2011).
The resurgence of covalent drugs.
  Nat Rev Drug Discov, 10, 307-317.  
21822280 L.Z.Mi, C.Lu, Z.Li, N.Nishida, T.Walz, and T.A.Springer (2011).
Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor.
  Nat Struct Mol Biol, 18, 984-989.  
21140395 M.Krug, K.Wichapong, G.Erlenkamp, W.Sippl, C.Schächtele, F.Totzke, and A.Hilgeroth (2011).
Discovery of 4-benzylamino-substituted α-carbolines as a novel class of receptor tyrosine kinase inhibitors.
  ChemMedChem, 6, 63-72.  
20938978 M.Mustafa, A.Mirza, and N.Kannan (2011).
Conformational regulation of the EGFR kinase core by the juxtamembrane and C-terminal tail: a molecular dynamics study.
  Proteins, 79, 99.  
21333004 Y.Naruo, T.Nagashima, R.Ushikoshi-Nakayama, Y.Saeki, T.Nakakuki, T.Naka, H.Tanaka, S.F.Tsai, and M.Okada-Hatakeyama (2011).
Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity.
  BMC Syst Biol, 5, 29.  
20129249 A.B.Turke, K.Zejnullahu, Y.L.Wu, Y.Song, D.Dias-Santagata, E.Lifshits, L.Toschi, A.Rogers, T.Mok, L.Sequist, N.I.Lindeman, C.Murphy, S.Akhavanfard, B.Y.Yeap, Y.Xiao, M.Capelletti, A.J.Iafrate, C.Lee, J.G.Christensen, J.A.Engelman, and P.A.Jänne (2010).
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
  Cancer Cell, 17, 77-88.  
20489620 A.Marrari, J.C.Trent, and S.George (2010).
Personalized cancer therapy for gastrointestinal stromal tumor: synergizing tumor genotyping with imatinib plasma levels.
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21135887 A.Ocana, A.Pandiella, L.L.Siu, and I.F.Tannock (2010).
Preclinical development of molecular-targeted agents for cancer.
  Nat Rev Clin Oncol, 8, 200-209.  
20118985 D.Ercan, K.Zejnullahu, K.Yonesaka, Y.Xiao, M.Capelletti, A.Rogers, E.Lifshits, A.Brown, C.Lee, J.G.Christensen, D.J.Kwiatkowski, J.A.Engelman, and P.A.Jänne (2010).
Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor.
  Oncogene, 29, 2346-2356.  
20551942 D.L.Wheeler, E.F.Dunn, and P.M.Harari (2010).
Understanding resistance to EGFR inhibitors-impact on future treatment strategies.
  Nat Rev Clin Oncol, 7, 493-507.  
  20640225 D.S.Johnson, E.Weerapana, and B.F.Cravatt (2010).
Strategies for discovering and derisking covalent, irreversible enzyme inhibitors.
  Future Med Chem, 2, 949-964.  
21129606 G.Bronte, S.Rizzo, L.La Paglia, V.Adamo, S.Siragusa, C.Ficorella, D.Santini, V.Bazan, G.Colucci, N.Gebbia, and A.Russo (2010).
Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma.
  Cancer Treat Rev, 36, S21-S29.  
20836684 G.M.Higa, V.Singh, and J.Abraham (2010).
Biological considerations and clinical applications of new HER2-targeted agents.
  Expert Rev Anticancer Ther, 10, 1497-1509.  
20739887 I.Vivanco, and I.K.Mellinghoff (2010).
Epidermal growth factor receptor inhibitors in oncology.
  Curr Opin Oncol, 22, 573-578.  
20006486 K.K.Wong, J.A.Engelman, and L.C.Cantley (2010).
Targeting the PI3K signaling pathway in cancer.
  Curr Opin Genet Dev, 20, 87-90.  
20215532 L.Gossage, and T.Eisen (2010).
Targeting multiple kinase pathways: a change in paradigm.
  Clin Cancer Res, 16, 1973-1978.  
20443070 L.Toschi, and F.Cappuzzo (2010).
Impact of biomarkers on non-small cell lung cancer treatment.
  Target Oncol, 5, 5.  
20026433 M.J.Eck, and C.H.Yun (2010).
Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer.
  Biochim Biophys Acta, 1804, 559-566.  
20406974 M.J.Lazzara, K.Lane, R.Chan, P.J.Jasper, M.B.Yaffe, P.K.Sorger, T.Jacks, B.G.Neel, and D.A.Lauffenburger (2010).
Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations.
  Cancer Res, 70, 3843-3850.  
20553217 M.Reck (2010).
A major step towards individualized therapy of lung cancer with gefitinib: the IPASS trial and beyond.
  Expert Rev Anticancer Ther, 10, 955-965.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
  20044834 R.Krishnamurty, and D.J.Maly (2010).
Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.
  ACS Chem Biol, 5, 121-138.  
21080395 S.Klüter, J.R.Simard, H.B.Rode, C.Grütter, V.Pawar, H.C.Raaijmakers, T.A.Barf, M.Rabiller, W.A.van Otterlo, and D.Rauh (2010).
Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance.
  Chembiochem, 11, 2557-2566.
PDB code: 3lok
20538618 S.Whittaker, R.Kirk, R.Hayward, A.Zambon, A.Viros, N.Cantarino, A.Affolter, A.Nourry, D.Niculescu-Duvaz, C.Springer, and R.Marais (2010).
Gatekeeper mutations mediate resistance to BRAF-targeted therapies.
  Sci Transl Med, 2, 35ra41.  
20828404 T.Hu, and C.Li (2010).
Convergence between Wnt-β-catenin and EGFR signaling in cancer.
  Mol Cancer, 9, 236.  
20031962 T.Mitsudomi (2010).
Advances in target therapy for lung cancer.
  Jpn J Clin Oncol, 40, 101-106.  
20148858 W.J.Lan, G.K.Hao, J.Wang, R.H.Zhang, W.Lan, R.M.Wang, R.Sun, and T.F.Wang (2010).
Duplexed on-microbead binding assay for competitive inhibitor of epidermal growth factor receptor by quantitative flow cytometry.
  Basic Clin Pharmacol Toxicol, 107, 560-564.  
20966921 W.Pao, and J.Chmielecki (2010).
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.
  Nat Rev Cancer, 10, 760-774.  
20810646 W.W.Chen, M.Niepel, and P.K.Sorger (2010).
Classic and contemporary approaches to modeling biochemical reactions.
  Genes Dev, 24, 1861-1875.  
20338520 W.Zhou, W.Hur, U.McDermott, A.Dutt, W.Xian, S.B.Ficarro, J.Zhang, S.V.Sharma, J.Brugge, M.Meyerson, J.Settleman, and N.S.Gray (2010).
A structure-guided approach to creating covalent FGFR inhibitors.
  Chem Biol, 17, 285-295.  
20628392 Y.Loriot, P.Mordant, N.Dorvault, T.De la motte Rouge, J.Bourhis, J.C.Soria, and E.Deutsch (2010).
BMS-690514, a VEGFR and EGFR tyrosine kinase inhibitor, shows anti-tumoural activity on non-small-cell lung cancer xenografts and induces sequence-dependent synergistic effect with radiation.
  Br J Cancer, 103, 347-353.  
  21165163 Z.Zhang, A.L.Stiegler, T.J.Boggon, S.Kobayashi, and B.Halmos (2010).
EGFR-mutated lung cancer: a paradigm of molecular oncology.
  Oncotarget, 1, 497-514.  
19186126 A.Dixit, A.Torkamani, N.J.Schork, and G.Verkhivker (2009).
Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability.
  Biophys J, 96, 858-874.  
19714203 A.Dixit, and G.M.Verkhivker (2009).
Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.
  PLoS Comput Biol, 5, e1000487.  
19834613 A.Dixit, L.Yi, R.Gowthaman, A.Torkamani, N.J.Schork, and G.M.Verkhivker (2009).
Sequence and structure signatures of cancer mutation hotspots in protein kinases.
  PLoS One, 4, e7485.  
19680293 A.F.Gazdar (2009).
Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.
  Oncogene, 28, S24-S31.  
19081671 A.Torkamani, G.Verkhivker, and N.J.Schork (2009).
Cancer driver mutations in protein kinase genes.
  Cancer Lett, 281, 117-127.  
  20616912 C.Aggarwal, and H.Borghaei (2009).
Rational use of cetuximab in the treatment of advanced non-small cell lung cancer.
  Onco Targets Ther, 2, 251-260.  
19518076 C.Qiu, M.K.Tarrant, T.Boronina, P.A.Longo, J.M.Kavran, R.N.Cole, P.A.Cole, and D.J.Leahy (2009).
In vitro enzymatic characterization of near full length EGFR in activated and inhibited states.
  Biochemistry, 48, 6624-6632.  
19236156 E.A.Hopper-Borge, R.E.Nasto, V.Ratushny, L.M.Weiner, E.A.Golemis, and I.Astsaturov (2009).
Mechanisms of tumor resistance to EGFR-targeted therapies.
  Expert Opin Ther Targets, 13, 339-362.  
19648052 H.J.Broxterman, K.J.Gotink, and H.M.Verheul (2009).
Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib.
  Drug Resist Updat, 12, 114-126.  
19381876 H.J.Chen, T.S.Mok, Z.H.Chen, A.L.Guo, X.C.Zhang, J.Su, and Y.L.Wu (2009).
Clinicopathologic and molecular features of epidermal growth factor receptor T790M mutation and c-MET amplification in tyrosine kinase inhibitor-resistant chinese non-small cell lung cancer.
  Pathol Oncol Res, 15, 651-658.  
20082842 H.X.Chen, J.N.Cleck, R.Coelho, and J.E.Dancey (2009).
Epidermal growth factor receptor inhibitors: current status and future directions.
  Curr Probl Cancer, 33, 245-294.  
19378324 J.B.Cooper, and E.E.Cohen (2009).
Mechanisms of resistance to EGFR inhibitors in head and neck cancer.
  Head Neck, 31, 1086-1094.  
19584848 K.Dorans (2009).
Outpacing cancer.
  Nat Med, 15, 718-722.  
19164557 K.S.Gajiwala, J.C.Wu, J.Christensen, G.D.Deshmukh, W.Diehl, J.P.DiNitto, J.M.English, M.J.Greig, Y.A.He, S.L.Jacques, E.A.Lunney, M.McTigue, D.Molina, T.Quenzer, P.A.Wells, X.Yu, Y.Zhang, A.Zou, M.R.Emmett, A.G.Marshall, H.M.Zhang, and G.D.Demetri (2009).
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
  Proc Natl Acad Sci U S A, 106, 1542-1547.
PDB codes: 3g0e 3g0f
  19632948 K.S.Nguyen, S.Kobayashi, and D.B.Costa (2009).
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway.
  Clin Lung Cancer, 10, 281-289.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
  19759520 L.Regales, Y.Gong, R.Shen, E.de Stanchina, I.Vivanco, A.Goel, J.A.Koutcher, M.Spassova, O.Ouerfelli, I.K.Mellinghoff, M.F.Zakowski, K.A.Politi, and W.Pao (2009).
Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
  J Clin Invest, 119, 3000-3010.  
19276351 M.A.Seeliger, P.Ranjitkar, C.Kasap, Y.Shan, D.E.Shaw, N.P.Shah, J.Kuriyan, and D.J.Maly (2009).
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
  Cancer Res, 69, 2384-2392.
PDB codes: 3g6g 3g6h
19343035 M.S.Cragg, C.Harris, A.Strasser, and C.L.Scott (2009).
Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics.
  Nat Rev Cancer, 9, 321-326.  
20477507 M.Yamauchi, and N.Gotoh (2009).
Theme: oncology--molecular mechanisms determining the efficacy of EGF receptor-specific tyrosine kinase inhibitors help to identify biomarker candidates.
  Biomark Med, 3, 139-151.  
19077689 P.A.Insel, and H.H.Patel (2009).
Membrane rafts and caveolae in cardiovascular signaling.
  Curr Opin Nephrol Hypertens, 18, 50-56.  
19629074 P.A.Jänne, N.Gray, and J.Settleman (2009).
Factors underlying sensitivity of cancers to small-molecule kinase inhibitors.
  Nat Rev Drug Discov, 8, 709-723.  
18761339 R.Bose, and X.Zhang (2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
  Exp Cell Res, 315, 649-658.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19680295 R.Pérez-Soler (2009).
Individualized therapy in non-small-cell lung cancer: future versus current clinical practice.
  Oncogene, 28, S38-S45.  
19627157 T.E.Balius, and R.C.Rizzo (2009).
Quantitative prediction of fold resistance for inhibitors of EGFR.
  Biochemistry, 48, 8435-8448.  
19105704 T.Hida, S.Ogawa, J.C.Park, J.Y.Park, J.Shimizu, Y.Horio, and K.Yoshida (2009).
Gefitinib for the treatment of non-small-cell lung cancer.
  Expert Rev Anticancer Ther, 9, 17-35.  
19176456 T.Negri, G.M.Pavan, E.Virdis, A.Greco, M.Fermeglia, M.Sandri, S.Pricl, M.A.Pierotti, S.Pilotti, and E.Tamborini (2009).
T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense.
  J Natl Cancer Inst, 101, 194-204.  
20033049 W.Zhou, D.Ercan, L.Chen, C.H.Yun, D.Li, M.Capelletti, A.B.Cortot, L.Chirieac, R.E.Iacob, R.Padera, J.R.Engen, K.K.Wong, M.J.Eck, N.S.Gray, and P.A.Jänne (2009).
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
  Nature, 462, 1070-1074.
PDB code: 3ika
18493974 A.Wissner, and T.S.Mansour (2008).
The development of HKI-272 and related compounds for the treatment of cancer.
  Arch Pharm (Weinheim), 341, 465-477.  
19010912 C.A.Pratilas, A.J.Hanrahan, E.Halilovic, Y.Persaud, J.Soh, D.Chitale, H.Shigematsu, H.Yamamoto, A.Sawai, M.Janakiraman, B.S.Taylor, W.Pao, S.Toyooka, M.Ladanyi, A.Gazdar, N.Rosen, and D.B.Solit (2008).
Genetic predictors of MEK dependence in non-small cell lung cancer.
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18981003 D.B.Costa, K.S.Nguyen, B.C.Cho, L.V.Sequist, D.M.Jackman, G.J.Riely, B.Y.Yeap, B.Halmos, J.H.Kim, P.A.Jänne, M.S.Huberman, W.Pao, D.G.Tenen, and S.Kobayashi (2008).
Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.
  Clin Cancer Res, 14, 7060-7067.  
18950281 E.Marrer, and F.Dieterle (2008).
Biomarkers in oncology drug development: rescuers or troublemakers?
  Expert Opin Drug Metab Toxicol, 4, 1391-1402.  
19010870 J.Bean, G.J.Riely, M.Balak, J.L.Marks, M.Ladanyi, V.A.Miller, and W.Pao (2008).
Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma.
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  19037833 M.Arkin, and M.M.Moasser (2008).
HER-2-directed, small-molecule antagonists.
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18794843 M.Azam, M.A.Seeliger, N.S.Gray, J.Kuriyan, and G.Q.Daley (2008).
Activation of tyrosine kinases by mutation of the gatekeeper threonine.
  Nat Struct Mol Biol, 15, 1109-1118.
PDB codes: 3dqw 3dqx
  18645621 X.Zhang, and A.Chang (2008).
Molecular predictors of EGFR-TKI sensitivity in advanced non-small cell lung cancer.
  Int J Med Sci, 5, 209-217.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.