Abstract
BackgroundSearching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1α (HIF-1α) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR.ResultsWe found that, compared with previously studied response markers, including EGFR per se and three EGFR downstream signal molecules (ERK, Akt, and STAT3), which showed variable post-treatment changes in levels of phosphorylation and no consistent link of the changes to therapeutic responses, HIF-1α showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1α downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1α mutant (HIF-1α/ΔODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1α/ΔODD-transfected cells remained sensitive to cetuximab-induced inhibition of Akt and ERK phosphorylation but were remarkably less responsive to cetuximab-induced growth inhibition compared with corresponding control cells.ConclusionOur data indicates that downregulation of HIF-1α is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1α as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting.
Highlights
Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted
We found in this study that post-treatment downregulation of hypoxia-inducible factor-1α (HIF-1α) was more consistently associated with cellular response than were the biochemical changes of extracellular signaling-related kinase (ERK) and Akt or that of STAT3, another downstream signaling molecule commonly activated by EGFR
We used a group of cancer cell lines with either overexpressed or tyrosine kinase domain-mutated (∆E746-A750 or L858R) EGFR to assess their responsiveness to cetuximab and gefitinib treatment and to evaluate HIF-1α as novel molecular marker for the therapeutic responses of the cancer cells to EGFR-targeted therapy
Summary
Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1α (HIF-1α) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR. Molecular Cancer 2007, 6:63 http://www.molecular-cancer.com/content/6/1/63 targeting EGFR with receptor-blocking monoclonal antibodies such as cetuximab and panitumumab, or with small-molecule EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, is effective against several types of solid tumors [5,6,7,8,9]. Exploration of the genetic and biochemical determinants of response to the therapy may help identifying patients who would benefit from EGFRtargeted therapy and may help in the design of co-targeting strategies to improve treatment effectiveness in patients who do not experience an optimal response to EGFR-targeted therapy alone
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