KEGG   PATHWAY: hsa01521Help
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
BRITE hierarchy
Pathway map
hsa01521  EGFR tyrosine kinase inhibitor resistance
hsa01521

Ortholog table
Drug
D08950  Neratinib (USAN/INN)
D10766  Osimertinib mesylate (USAN)
D10898  Neratinib maleate
D11239  Lumretuzumab (USAN/INN)
D11244  Vanucizumab (USAN/INN)
D11251  Icotinib
D11307  Telisotuzumab (USAN)
D11344  Telisotuzumab vedotin (USAN)
D11417  Pemigatinib (USAN/INN)
D11529  Trastuzumab deruxtecan (genetical recombination) (JAN)
Organism
Homo sapiens (human) [GN:hsa]
Reference
  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
  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
  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
  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
  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
  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
  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
  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(1):13-19 (2013)
DOI:10.14259/or.v1i1.81
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Arteaga CL
  Title
HER3 and mutant EGFR meet MET.
  Journal
Nat Med 13:675-7 (2007)
DOI:10.1038/nm0607-675
KO pathway
ko01521   

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