A33
Effects of lapatinib on the metabolic profile of NEU/HER2 overexpressing mammary tumours in MMTV-NEU-NT mice measured by in vitro 1H and 31P magnetic resonance spectroscopy
Loreta Rodrigues, Basetti Madhu, John Griffiths
Cambridge Research Institute, Cambridge, UK
Background
Overexpression of HER2 is seen in approximately 25-30% of human breast cancers and is associated with a more malignant phenotype and worse prognosis. Lapatinib, a small-molecule dual tyrosine kinase inhibitor, blocks downstream signalling pathways of HER2 and EGFR selectively, through inhibition of autophosphorylation sites on the receptor, and this combined inhibition of both EGFR and HER2 may be more efficient than either alone. Lapatinib has been shown to have preclinical and clinical activity in HER2-positive breast cancer1,2.
Method
In this study we used 1H and 31P magnetic resonance spectroscopy (MRS) to assess the short term effects of lapatinib on the metabolic profile of mammary adenocarcinomas in transgenic mice that overexpress HER2. Tumour-bearing mice received a daily intraperitoneal dose of lapatinib (100mg/kg) for 4 days and tumours were snap-frozen on day 5. Tumour volume was measured pre and post- treatment. 1H and 31P MRS were performed on the neutralised tumour extracts using a 600MHz Bruker system.
Results and Conclusion
The tumour volume 5 days post-treatment showed a significant decrease (88 3.3%, p<0.01) when compared to either the pre-treatment volume (100%) or the tumour volume in the control group at day 5 (112.1 3.1%, p<0.001). There was no change in the glucose, lactate or alanine concentration and therefore no change in the glycolytic coefficient of these tumours post-treatment. Elevated total choline (sum of phosphocholine (PC), glycerophosphocholine (GPC) and free choline) and phosphocholine (PC) are widely established characteristics of cancer cells, and increased phospholipd turnover is a significant metabolic pathway during tumour development3. Here we observed a significant decrease (p<0.03) in GPC and in total choline post short term treatment with lapatinib, demonstrating that the precursors and catabolites of this pathway can provide early and useful biomarkers of response to treatment with lapatinib and suggesting that choline phospholipid metabolism could be a target for therapy.
References
[1] GE Konecny et al, Cancer Res, 66, 1630-39 (2006).
[2] Geyer MD et al, N Engl J Med, 355, 2733-43 (2006).
[3] Ackerstaff E et al, J Cell Biochem, 90, 525-533 (2003).
