title: Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors and Therapeutic Approaches: An Update.
abstract: Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non small cell lung cancer (NSCLC) is mediated by two major mechanisms namely secondary mutation T790M in EGFR and cMET amplification. Other molecular mediators which contribute towards TKI resistance include the activation of compensatory growth signaling, epithelial mesenchymal transition and microRNAs regulating EGFR and cMET levels. In this chapter, we have included the major mechanisms which contribute towards EGFR TKI resistance in NSCLC. Several therapeutic approaches to overcome TKI resistance are also presented which include second and third generation EGFR TKI inhibitors and cMET inhibitors. Further, the rationale to utilize the combination therapies to simultaneously target EGFR and other major oncogene addictive pathway such as ERBB2 and AXL kinase is outlined. Another promising approach to overcome TKI resistance is to potentiate EGFR protein for degradation. These studies will best be utilized when we can identify the oncogene addictions in an individual patient and tailor the therapy/therapies accordingly for the maximum benefits.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA. aarif.ahsan@pfizer.com.|Bioconjugate Drug Discovery, Oncology Research Unit, Pfizer Inc., 401 N. Middletown Rd., Pearl River, NY, 10965, USA. aarif.ahsan@pfizer.com.
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: EGFR; Erlotinib; Non small cell lung cancer; TKI resistance; cMET