title: Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors.
abstract: BACKGROUND
  Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.
  
  
  METHODS
  This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation.
  
  
  CONCLUSIONS
  Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.
authors: Phase I - Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium. Electronic address: christian.rolfo@uza.be.
authors: Christian
authors: C
authors: Rolfo
authors: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Elisa
authors: E
authors: Giovannetti
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: David S
authors: DS
authors: Hong
authors: Hematology and Oncology Department, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors: T
authors: T
authors: Bivona
authors: Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA.
authors: Luis E
authors: LE
authors: Raez
authors: Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors: Giuseppe
authors: G
authors: Bronte
authors: San Giovanni Battista Molinette Hospital, Department of Medical Oncology, Turin, Italy.
authors: Lucio
authors: L
authors: Buffoni
authors: Medical Oncology Department, Hospital Clinic, Barcelona, Spain.
authors: Noemí
authors: N
authors: Reguart
authors: Lynn Cancer Institute, Thoracic Oncology, Boca Raton, FL, USA.
authors: Edgardo S
authors: ES
authors: Santos
authors: Department of Respiratory Medicine, AZ Maria Middelares, Kortrijksesteenweg 1026, 9000 Ghent, Belgium.
authors: Paul
authors: P
authors: Germonpre
authors: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors: Mìquel
authors: M
authors: Taron
authors: Phase I - Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium; Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors: Francesco
authors: F
authors: Passiglia
authors: Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium.
authors: Jan P
authors: JP
authors: Van Meerbeeck
authors: Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors: Antonio
authors: A
authors: Russo
authors: Department of Medical Oncology, University Hospital Antwerpen, Wilrijkstraat 10, 2650 Edegem, Belgium.
authors: Marc
authors: M
authors: Peeters
authors: Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain.
authors: Ignacio
authors: I
authors: Gil-Bazo
authors: Molecular Pathology Unit, Pathology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium.
authors: Patrick
authors: P
authors: Pauwels
authors: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors: Rafael
authors: R
authors: Rosell
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR mutations; NSCLC; New drugs; Novel therapeutic strategies; TKI inhibitors resistance