Open AccessThe glucose‐deprivation network counteracts lapatinib‐induced toxicity in resistant ErbB2‐positive breast cancer cells
Author(s) -
Komurov Kakajan,
Tseng JenTe,
Muller Melissa,
Seviour Elena G,
Moss Tyler J,
Yang Lifeng,
Nagrath Deepak,
Ram Prahlad T
Publication year - 2012
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2012.25
Subject(s) - lapatinib , biology , cancer , glucose homeostasis , cancer research , pharmacology , breast cancer , insulin resistance , endocrinology , insulin , genetics , trastuzumab
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.