BACKGROUND: Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinical roles based on their efficacy in a subset of cancers, generally as components of combination therapies. Many cancers are either initially resistant to EGFR inhibitors or become resistant during treatment, limiting the efficacy of these reagents. OBJECTIVE/ METHODS: To review cellular resistance mechanisms to EGFR-targeted therapies. RESULTS/ CONCLUSIONS: The best validated of these mechanisms include activation of classic ATP-binding casette (ABC) multidrug transporters; activation or mutation of EGFR; and overexpression or activation of signaling proteins operating in relation to EGFR. We discuss current efforts and potential strategies to override these sources of resistance. We describe emerging systems-biology-based concepts of alternative resistance to EGFR-targeted therapies, and discuss their implications for use of EGFR-targeted and other targeted therapies.
BACKGROUND: Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinical roles based on their efficacy in a subset of cancers, generally as components of combination therapies. Many cancers are either initially resistant to EGFR inhibitors or become resistant during treatment, limiting the efficacy of these reagents. OBJECTIVE/ METHODS: To review cellular resistance mechanisms to EGFR-targeted therapies. RESULTS/ CONCLUSIONS: The best validated of these mechanisms include activation of classic ATP-binding casette (ABC) multidrug transporters; activation or mutation of EGFR; and overexpression or activation of signaling proteins operating in relation to EGFR. We discuss current efforts and potential strategies to override these sources of resistance. We describe emerging systems-biology-based concepts of alternative resistance to EGFR-targeted therapies, and discuss their implications for use of EGFR-targeted and other targeted therapies.
Authors: Michael S Gordon; Daniela Matei; Carol Aghajanian; Ursula A Matulonis; Molly Brewer; Gini F Fleming; John D Hainsworth; Agustin A Garcia; Mark D Pegram; Russell J Schilder; David E Cohn; Lynda Roman; Mika K Derynck; Kimmie Ng; Benjamin Lyons; David E Allison; David A Eberhard; Thinh Q Pham; Randall C Dere; Beth Y Karlan Journal: J Clin Oncol Date: 2006-08-08 Impact factor: 44.544
Authors: P A Humphrey; L M Gangarosa; A J Wong; G E Archer; M Lund-Johansen; R Bjerkvig; O D Laerum; H S Friedman; D D Bigner Journal: Biochem Biophys Res Commun Date: 1991-08-15 Impact factor: 3.575
Authors: John C Sok; Francesca M Coppelli; Sufi M Thomas; Miriam N Lango; Sichuan Xi; Jennifer L Hunt; Maria L Freilino; Michael W Graner; Carol J Wikstrand; Darell D Bigner; William E Gooding; Frank B Furnari; Jennifer R Grandis Journal: Clin Cancer Res Date: 2006-09-01 Impact factor: 12.531
Authors: Miguel Angel Pujana; Jing-Dong J Han; Lea M Starita; Kristen N Stevens; Muneesh Tewari; Jin Sook Ahn; Gad Rennert; Víctor Moreno; Tomas Kirchhoff; Bert Gold; Volker Assmann; Wael M Elshamy; Jean-François Rual; Douglas Levine; Laura S Rozek; Rebecca S Gelman; Kristin C Gunsalus; Roger A Greenberg; Bijan Sobhian; Nicolas Bertin; Kavitha Venkatesan; Nono Ayivi-Guedehoussou; Xavier Solé; Pilar Hernández; Conxi Lázaro; Katherine L Nathanson; Barbara L Weber; Michael E Cusick; David E Hill; Kenneth Offit; David M Livingston; Stephen B Gruber; Jeffrey D Parvin; Marc Vidal Journal: Nat Genet Date: 2007-10-07 Impact factor: 38.330
Authors: Roberto Bianco; Incheol Shin; Christoph A Ritter; F Michael Yakes; Andrea Basso; Neal Rosen; Junji Tsurutani; Phillip A Dennis; Gordon B Mills; Carlos L Arteaga Journal: Oncogene Date: 2003-05-08 Impact factor: 9.867
Authors: Tetyana V Bagnyukova; Ilya G Serebriiskii; Yan Zhou; Elizabeth A Hopper-Borge; Erica A Golemis; Igor Astsaturov Journal: Cancer Biol Ther Date: 2010-11-01 Impact factor: 4.742
Authors: Igor Astsaturov; Vladimir Ratushny; Anna Sukhanova; Margret B Einarson; Tetyana Bagnyukova; Yan Zhou; Karthik Devarajan; Joshua S Silverman; Nadezhda Tikhmyanova; Natalya Skobeleva; Anna Pecherskaya; Rochelle E Nasto; Catherine Sharma; Sandra A Jablonski; Ilya G Serebriiskii; Louis M Weiner; Erica A Golemis Journal: Sci Signal Date: 2010-09-21 Impact factor: 8.192