Weaver Z, et al., Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response. Cancer Research, 2012. 72(22): 5921-5933.
Metabolon results led to:
- Biomarkers in the mouse that could stratify patient responses to cancer treatments
- Identification of biochemical pathways uniquely responsive to combination therapy
- New targets to combat acquired chemotherapy resistance
Key metabolomic observations:
- Pyruvate and UDP-GlcNAc were restored to non-cancerous levels with combination therapy, but not with individual chemotherapy treatments
- Upregulated glutathione synthesis was revealed as a possible mediator of EGFR oncogenesis
Lung cancers caused by activating mutations in EGFR frequently become resistant to tyrosine kinase inhibitors (TKI), but often remain sensitive to rapamycin-TKI combination therapy. In a mouse model of EGFR-driven TKI-resistant lung adenocarcinoma, integrative transcriptomics and metabolomics analysis identified pathways that were activated with cancer development. While individual chemotherapy treatments temporarily restored many metabolites to non-cancerous levels, a subset of metabolites were restored to non-cancerous levels only with combination therapy, suggesting that these pathways were involved in acquired resistance to individual chemotherapy treatments. These results illustrate that metabolite profiling can identify molecular markers that (1) track cancer onset and progression (2) predict and monitor patient responses to chemotherapies and (3) identify new targets to combat acquired resistance to chemotherapies.