ENTRY       hsa01521                    Pathway
NAME        EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)
DESCRIPTION EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR also serves as a stimulus for cancer growth. EGFR gene mutations and protein overexpression, both of which activate down- stream pathways, are associated with cancers, especially lung cancer. Several tyrosine kinase inhibitor (TKI) therapies against EGFR are currently administered and are initially effective in cancer patients who have EGFR mutations or aberrant activation of EGFR. However, the development of TKI resistance is common and results in the recurrence of tumors. Studies over the last decade have identified mechanisms that drive resistance to EGFR TKI treatment. Most outstanding mechanisms are: the secondary EGFR mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, etc.
CLASS       Human Diseases; Drug resistance: antineoplastic
PATHWAY_MAP hsa01521  EGFR tyrosine kinase inhibitor resistance
DRUG        D08950  Neratinib (USAN/INN)
            D09371  Ramucirumab (USAN)
            D10766  Osimertinib mesylate (USAN)
            D10898  Neratinib maleate
            D11244  Vanucizumab (USAN/INN)
            D11251  Icotinib
            D11307  Telisotuzumab (USAN)
            D11344  Telisotuzumab vedotin (USAN)
            D11417  Pemigatinib (JAN/USAN/INN)
            D11529  Trastuzumab deruxtecan (USAN/INN)
            D11725  Futibatinib (JAN/USAN/INN)
            D11772  Tesevatinib (USAN/INN)
            D11773  Tesevatinib tosylate (USAN)
            D11969  Mobocertinib succinate (JAN)
            D11980  Lazertinib (USAN)
            D12219  Mecbotamab (USAN)
            D12220  Mecbotamab vedotin
            D12245  Lazertinib mesilate hydrate (JAN)
            D12258  Aumolertinib (USAN)
            D12259  Aumolertinib mesylate (USAN)
ORGANISM    Homo sapiens (human) [GN:hsa]
REFERENCE   PMID:26579470
  AUTHORS   Huang L, Fu L
  TITLE     Mechanisms of resistance to EGFR tyrosine kinase inhibitors.
  JOURNAL   Acta Pharm Sin B 5:390-401 (2015)
            DOI:10.1016/j.apsb.2015.07.001
REFERENCE   PMID:23358468
  AUTHORS   Hrustanovic G, Lee BJ, Bivona TG
  TITLE     Mechanisms of resistance to EGFR targeted therapies.
  JOURNAL   Cancer Biol Ther 14:304-14 (2013)
            DOI:10.4161/cbt.23627
REFERENCE   PMID:25232485
  AUTHORS   Lin Y, Wang X, Jin H
  TITLE     EGFR-TKI resistance in NSCLC patients: mechanisms and strategies.
  JOURNAL   Am J Cancer Res 4:411-35 (2014)
REFERENCE   PMID:19632948
  AUTHORS   Nguyen KS, Kobayashi S, Costa DB
  TITLE     Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway.
  JOURNAL   Clin Lung Cancer 10:281-9 (2009)
            DOI:10.3816/CLC.2009.n.039
REFERENCE   PMID:18483355
  AUTHORS   Engelman JA, Janne PA
  TITLE     Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.
  JOURNAL   Clin Cancer Res 14:2895-9 (2008)
            DOI:10.1158/1078-0432.CCR-07-2248
REFERENCE   PMID:23401451
  AUTHORS   Ohashi K, Maruvka YE, Michor F, Pao W
  TITLE     Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease.
  JOURNAL   J Clin Oncol 31:1070-80 (2013)
            DOI:10.1200/JCO.2012.43.3912
REFERENCE   PMID:24307395
  AUTHORS   Carrera S, Buque A, Azkona E, Aresti U, Calvo B, Sancho A, Arruti M, Nuno M, Rubio I, de Lobera AR, Lopez C, Vivanco GL
  TITLE     Epidermal growth factor receptor tyrosine-kinase inhibitor treatment resistance in non-small cell lung cancer: biological basis and therapeutic strategies.
  JOURNAL   Clin Transl Oncol 16:339-50 (2014)
            DOI:10.1007/s12094-013-1143-9
REFERENCE   PMID:22970367
  AUTHORS   Lin L, Bivona TG
  TITLE     Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients.
  JOURNAL   Chemother Res Pract 2012:817297 (2012)
            DOI:10.1155/2012/817297
REFERENCE   
  AUTHORS   Song X.
  TITLE     Targeting PI3K/AKT/mTOR pathway and mutant EGFR to overcome resistance to tyrosine kinase inhibitors in mutant EGFR-mediated lung cancer
  JOURNAL   Onco Reviews 1:13-19 (2013)
            DOI:10.14259/or.v1i1.81
REFERENCE   PMID:24202392
  AUTHORS   Chong CR, Janne PA
  TITLE     The quest to overcome resistance to EGFR-targeted therapies in cancer.
  JOURNAL   Nat Med 19:1389-400 (2013)
            DOI:10.1038/nm.3388
REFERENCE   PMID:20551942
  AUTHORS   Wheeler DL, Dunn EF, Harari PM
  TITLE     Understanding resistance to EGFR inhibitors-impact on future treatment strategies.
  JOURNAL   Nat Rev Clin Oncol 7:493-507 (2010)
            DOI:10.1038/nrclinonc.2010.97
REFERENCE   PMID:23361103
  AUTHORS   Gonzalez de Castro D, Clarke PA, Al-Lazikani B, Workman P
  TITLE     Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance.
  JOURNAL   Clin Pharmacol Ther 93:252-9 (2013)
            DOI:10.1038/clpt.2012.237
REFERENCE   PMID:20966921
  AUTHORS   Pao W, Chmielecki J
  TITLE     Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.
  JOURNAL   Nat Rev Cancer 10:760-74 (2010)
            DOI:10.1038/nrc2947
REFERENCE   PMID:22956644
  AUTHORS   Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, Riely GJ, Kris MG, Miller VA, Ladanyi M, Politi K, Pao W
  TITLE     HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
  JOURNAL   Cancer Discov 2:922-33 (2012)
            DOI:10.1158/2159-8290.CD-12-0108
REFERENCE   PMID:16843264
  AUTHORS   Zhou BB, Peyton M, He B, Liu C, Girard L, Caudler E, Lo Y, Baribaud F, Mikami I, Reguart N, Yang G, Li Y, Yao W, Vaddi K, Gazdar AF, Friedman SM, Jablons DM, Newton RC, Fridman JS, Minna JD, Scherle PA
  TITLE     Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.
  JOURNAL   Cancer Cell 10:39-50 (2006)
            DOI:10.1016/j.ccr.2006.05.024
REFERENCE   PMID:22474259
  AUTHORS   Logue JS, Morrison DK
  TITLE     Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy.
  JOURNAL   Genes Dev 26:641-50 (2012)
            DOI:10.1101/gad.186965.112
REFERENCE   PMID:24493829
  AUTHORS   Costa C, Molina MA, Drozdowskyj A, Gimenez-Capitan A, Bertran-Alamillo J, Karachaliou N, Gervais R, Massuti B, Wei J, Moran T, Majem M, Felip E, Carcereny E, Garcia-Campelo R, Viteri S, Taron M, Ono M, Giannikopoulos P, Bivona T, Rosell R
  TITLE     The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial.
  JOURNAL   Clin Cancer Res 20:2001-10 (2014)
            DOI:10.1158/1078-0432.CCR-13-2233
REFERENCE   PMID:23071030
  AUTHORS   Blakely CM, Bivona TG
  TITLE     Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance.
  JOURNAL   Cancer Discov 2:872-5 (2012)
            DOI:10.1158/2159-8290.CD-12-0387
REFERENCE   PMID:25337673
  AUTHORS   Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B
  TITLE     AXL kinase as a novel target for cancer therapy.
  JOURNAL   Oncotarget 5:9546-63 (2014)
            DOI:10.18632/oncotarget.2542
REFERENCE   PMID:17554333
  AUTHORS   Arteaga CL
  TITLE     HER3 and mutant EGFR meet MET.
  JOURNAL   Nat Med 13:675-7 (2007)
            DOI:10.1038/nm0607-675
REL_PATHWAY hsa04010  MAPK signaling pathway
            hsa04012  ErbB signaling pathway
            hsa04150  mTOR signaling pathway
            hsa04151  PI3K-Akt signaling pathway
            hsa04210  Apoptosis
            hsa04630  JAK-STAT signaling pathway
            hsa05212  Pancreatic cancer
            hsa05214  Glioma
            hsa05223  Non-small cell lung cancer
KO_PATHWAY  ko01521
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