title: Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients.
  
  
  METHODS
  We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed.
  
  
  CONCLUSIONS
  We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M+MET gene copy number gain, and mutant EGFR loss+unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p=0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan. Electronic address: ascaris@surg2.med.kyushu-u.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.affiliation: Department of Respiratory Medicine, Higashi-Hiroshima Medical Center, 513 Jike, Saijo-Cho, Higashi-Hiroshima, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Murakami
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomizawa
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuuchi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D015331:Cohort Studies; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D018773:Genes, erbB-1; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage; D016019:Survival Analysis; D061665:Time-to-Treatment / Q000639:trends; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib
keywords: Acquired resistance; Autopsy; EGFR mutation; Gefitinib; Molecular target therapy; T790M mutation