Researchers have used computational analysis to identify a new Achilles
heel for the treatment of drug-resistant breast cancer. The results,
which are published in Molecular Systems Biology, reveal that
the disruption of glucose metabolism is an effective therapeutic
strategy for the treatment of tumours that have acquired resistance to
front-line cancer drugs such as Lapatinib.
“The growth and survival of cancer cells can often be impaired by
treatment with drugs that interfere with the actions of one or more
oncogenes,” said Prahlad Ram, the senior author of the study and
Professor at the University of Texas MD Anderson Cancer Center, Houston,
Texas. “However, the clinical benefits to patients are often short
lived due to acquired drug resistance. Finding alternative intervention
points or so-called new addictions for cancer cells is of critical
importance for designing novel therapeutic strategies against tumours.
Our results reveal specific new targets for drug intervention in the
metabolic pathways of cancer cells and identify existing drugs that can
be used to treat drug-resistant cancer.”
Lapatinib is used for the treatment of patients with advanced or
metastatic breast cancer in cases where tumours overexpress the ErbB2
gene. The ErbB2 gene provides instructions for making a specific growth
factor receptor. If too much of this ErbB2 growth factor receptor is
made, it can lead to cells that grow and divide continuously, one of the
defining characteristics of breast cancer.
The scientists used microarrays to measure gene expression in breast
cancer cells with and without treatment with Lapatinib. Computational
analysis of more than 15000 gene interactions revealed four major
populations of genes that were regulated in a significant way. Three of
these groups were the regular suspects related to drug resistance, such
as genes involved in oxidation and reduction reactions or cell cycle
processes. A fourth group comprised a network of reactions linked to the
deprivation of glucose.
Analysis of the gene expression networks of ErbB2-positive breast
cancer patients revealed that the glucose deprivation network is linked
to low survival rates of the patients. Computational screening of a
library of existing drugs for therapeutics that target the glucose
deprivation response identified several drugs that could be effective in
treating drug-resistant breast cancer.
“By developing novel gene expression analysis algorithms and
integrating diverse data, we have been able to look beyond changes in
the immediate molecular signaling pathways of breast cancer cells and to
consider the wider system of molecular networks within the cell,”
remarked Ram. “Our approach predicts new uses for existing drugs that
impact the metabolism of breast cancer cells and may offer an expedient
route to improved treatments for breast cancer patients.”
Journal Reference:
- Kakajan Komurov, Jen-Te Tseng, Melissa Muller, Elena G Seviour, Tyler J Moss, Lifeng Yang, Deepak Nagrath, Prahlad T Ram. The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ErbB2-positive breast cancer cells. Molecular Systems Biology, 2012; 8 DOI: 10.1038/msb.2012.25
Courtesy: ScienceDaily
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