Dynamic interactions between intracellular
networks regulate cellular homeostasis and responses to perturbations. Targeted
therapy is aimed at perturbing oncogene addiction pathways in cancer, however,
development of acquired resistance to these drugs is a significant clinical
problem. A network-based computational analysis of global gene expression data
from matched sensitive and acquired drug-resistant cells to lapatinib, an
EGFR/ErbB2 inhibitor, revealed an increased expression of the glucose
deprivation response network, including glucagon signaling, glucose uptake,
gluconeogenesis and unfolded protein response in the resistant cells.
Importantly, the glucose deprivation response markers correlated significantly
with high clinical relapse rates in ErbB2-positive breast cancer patients.
Further, forcing drug-sensitive cells into glucose deprivation rendered them
more resistant to lapatinib. Using a chemical genomics bioinformatics mining of
the CMAP database, we identified drugs that specifically target the glucose
deprivation response networks to overcome the resistant phenotype and reduced
survival of resistant cells. This study implicates the chronic activation of
cellular compensatory networks in response to targeted therapy and suggests
novel combinations targeting signaling and metabolic networks in tumors with
acquired resistance.
Source: The glucose-deprivation
network counteracts lapatinib-induced toxicity in resistant ErbB2-positive
breast cancer cells. Komurov K, Tseng JT, Muller M, Seviour EG, Moss TJ, Yang
L, Nagrath D, Ram PT. Mol Syst Biol. 2012 Jul 31;8:596.
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