Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer.
The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-κB activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transition, PDL1 expression with subsequent immune tolerance, and release of cytokines such as TGFβ and IL6. Herein, we review the growing body of knowledge regarding EGFR bypass pathways, and the development of new drugs and combination treatment strategies to overcome resistance. Mol Cancer Ther; 16(2); 265-72. ©2017 AACR.
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California. rkurzrock@ucsd.edu hhusain@ucsd.edu.
Hatim
H
Husain
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Michael
M
Scur
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Ayesha
A
Murtuza
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Nam
N
Bui
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California.
Brian
B
Woodward
Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California. rkurzrock@ucsd.edu hhusain@ucsd.edu.
Razelle
R
Kurzrock
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D002352:Carrier Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; D015415:Biomarkers; D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors