title: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
abstract: Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
authors: Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. lvsequist@partners.org
authors: Lecia V
authors: LV
authors: Sequist
authors: Belinda A
authors: BA
authors: Waltman
authors: Dora
authors: D
authors: Dias-Santagata
authors: Subba
authors: S
authors: Digumarthy
authors: Alexa B
authors: AB
authors: Turke
authors: Panos
authors: P
authors: Fidias
authors: Kristin
authors: K
authors: Bergethon
authors: Alice T
authors: AT
authors: Shaw
authors: Scott
authors: S
authors: Gettinger
authors: Arjola K
authors: AK
authors: Cosper
authors: Sara
authors: S
authors: Akhavanfard
authors: Rebecca S
authors: RS
authors: Heist
authors: Jennifer
authors: J
authors: Temel
authors: James G
authors: JG
authors: Christensen
authors: John C
authors: JC
authors: Wain
authors: Thomas J
authors: TJ
authors: Lynch
authors: Kathy
authors: K
authors: Vernovsky
authors: Eugene J
authors: EJ
authors: Mark
authors: Michael
authors: M
authors: Lanuti
authors: A John
authors: AJ
authors: Iafrate
authors: Mari
authors: M
authors: Mino-Kenudson
authors: Jeffrey A
authors: JA
authors: Engelman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001706:Biopsy; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib