The glucose‐deprivation network counteracts lapatinib‐induced toxicity in resistant ErbB2‐positive breast cancer cells

Molecular Systems Biology

Kakajan Komurov¹  Jen-Te Tseng¹  Melissa Muller¹  Elena G Seviour¹  Tyler J Moss¹  Lifeng Yang²  Deepak Nagrath² 

[1] Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Chemical and Biomolecular Engineering Department, Rice University, Houston, TX, USA

关键词: bioinformatics;    computational methods;    functional genomics;    metabolic and regulatory networks;    signal transduction;   

DOI  :  10.1038/msb.2012.25

来源: Wiley

【 摘 要 】

Abstract

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.

Synopsis

This study implicates the glucose deprivation response in breast cancer cell resistance to lapatinib and high relapse rates in Her2-positive patients. Identification of these compensatory networks suggests novel strategies to target cancer signaling and metabolism.

• Increased expression of the glucose deprivation response network, including glucagon signaling, glucose uptake, gluconeogenesis and unfolded protein response genes is found in breast cancer cells with acquired resistance to lapatinib.
• The glucose deprivation response gene network correlated significantly with high clinical relapse rates in ErbB2-positive breast cancer patients.
• Chemical genomics bioinformatics data mining identified drugs that target the glucose deprivation response networks to reduced survival of resistant cells.

【 授权许可】

CC BY-NC-SA   
Copyright © 2012 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.