Temporal molecular and biological assessment of an erlotinib-resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response
Menée à l'aide d'un modèle murin d'adénocarcinome du poumon résistant à l'erlotinib, cette étude identifie, de façon dynamique au cours de traitements administrés seuls ou en combinaison, l'évolution de métabolites marqueurs de la réponse thérapeutique
Lung cancer patients with activating mutations in the epidermal growth factor receptor (EGFR) kinase who are treated long-term with tyrosine kinase inhibitors (TKIs) 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. In order to correlate EGFR-driven changes in the lung with response to drug treatment, we performed an integrative analysis of global transcriptome and metabolite profiling compared to quantitative imaging and histopathology at several time points during tumor progression and treatment. Responses to single drug treatments were temporary, while combination therapy elicited a sustained response. During tumor development, metabolomic signatures indicated a shift to high anabolic activity and suppression of anti-tumor 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.
Cancer Research , résumé, 2012