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: Zoë Weaver, Simone Difilippantonio, Julian Carretero, Philip L Martin, Rajaa El Meskini, Anthony J Iacovelli, Michelle Gumprecht, Alan Kulaga, Theresa Guerin, Jerome Schlomer, Maureen Baran, Serguei Kozlov, Thomas McCann, Salvador Mena, Fatima Al-Shahrour, Danny Alexander, Kwok-Kin Wong, Terry Van Dyke
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 22 Pg. 5921-33 (Nov 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22969147 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2012 AACR.

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• Transcription Factors
• Afatinib
• Erlotinib Hydrochloride
• ErbB Receptors
• Sirolimus

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Adenocarcinoma of Lung
• Afatinib
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Growth Processes (physiology)
• Disease Progression
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Gene Expression
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (administration & dosage, pharmacology)
• Sirolimus (administration & dosage)
• Transcription Factors (genetics, metabolism)