title: Temporal molecular and biological assessment of an erlotinib-resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response.
abstract: Patients with lung cancer with activating mutations in the EGF receptor (EGFR) kinase, who are treated long-term with tyrosine kinase inhibitors (TKI), often develop secondary mutations in EGFR associated with resistance. Mice engineered to develop lung adenocarcinomas driven by the human EGFR T790M resistance mutation are similarly resistant to the EGFR TKI erlotinib. By tumor volume endpoint analysis, these mouse tumors respond to BIBW 2992 (an irreversible EGFR/HER2 TKI) and rapamycin combination therapy. To correlate EGFR-driven changes in the lung with response to drug treatment, we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment. Responses to single-drug treatments were temporary, whereas combination therapy elicited a sustained response. During tumor development, metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood. Combination drug treatment reversed many of the molecular changes found in tumored lung. Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments. Results from combination drug treatment suggest that metabolic transcriptional control through C-MYC and SREBP, as well as ELK1, NRF1, and NRF2, depends on both EGFR and mTORC1 signaling. Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI-mediated antiproliferative effects also manifest in specific metabolic regulation.
authors.affiliation: Center for Advanced Preclinical Research, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research/NCI, Frederick, Maryland 21702, USA.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Weaver
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Meskini
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iacovelli
authors.forename: Michelle
authors.initials: M
authors.lastname: Gumprecht
authors.forename: Alan
authors.initials: A
authors.lastname: Kulaga
authors.forename: Theresa
authors.initials: T
authors.lastname: Guerin
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlomer
authors.forename: Maureen
authors.initials: M
authors.lastname: Baran
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Thomas
authors.initials: T
authors.lastname: McCann
authors.forename: Salvador
authors.initials: S
authors.lastname: Mena
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Danny
authors.initials: D
authors.lastname: Alexander
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D048708:Cell Growth Processes / Q000502:physiology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014157:Transcription Factors; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020123:Sirolimus