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Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha.
Mol Cancer 2007; 6:63MC

Abstract

BACKGROUND

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-1alpha (HIF-1alpha) 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.

RESULTS

We 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-1alpha showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1alpha downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1alpha mutant (HIF-1alpha/DeltaODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1alpha/DeltaODD-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.

CONCLUSION

Our data indicates that downregulation of HIF-1alpha is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1alpha as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting.

Authors+Show Affiliations

Department of Experimental Therapeutics, The University of Texas M, D, Anderson Cancer Center, Houston, Texas 77030, USA. ylu@mdanderson.orgNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17931419

Citation

Lu, Yang, et al. "Responses of Cancer Cells With Wild-type or Tyrosine Kinase Domain-mutated Epidermal Growth Factor Receptor (EGFR) to EGFR-targeted Therapy Are Linked to Downregulation of Hypoxia-inducible Factor-1alpha." Molecular Cancer, vol. 6, 2007, p. 63.
Lu Y, Liang K, Li X, et al. Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha. Mol Cancer. 2007;6:63.
Lu, Y., Liang, K., Li, X., & Fan, Z. (2007). Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha. Molecular Cancer, 6, p. 63.
Lu Y, et al. Responses of Cancer Cells With Wild-type or Tyrosine Kinase Domain-mutated Epidermal Growth Factor Receptor (EGFR) to EGFR-targeted Therapy Are Linked to Downregulation of Hypoxia-inducible Factor-1alpha. Mol Cancer. 2007 Oct 11;6:63. PubMed PMID: 17931419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha. AU - Lu,Yang, AU - Liang,Ke, AU - Li,Xinqun, AU - Fan,Zhen, Y1 - 2007/10/11/ PY - 2007/08/11/received PY - 2007/10/11/accepted PY - 2007/10/13/pubmed PY - 2008/2/23/medline PY - 2007/10/13/entrez SP - 63 EP - 63 JF - Molecular cancer JO - Mol. Cancer VL - 6 N2 - BACKGROUND: 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-1alpha (HIF-1alpha) 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. RESULTS: We 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-1alpha showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1alpha downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1alpha mutant (HIF-1alpha/DeltaODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1alpha/DeltaODD-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. CONCLUSION: Our data indicates that downregulation of HIF-1alpha is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1alpha as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting. SN - 1476-4598 UR - https://www.unboundmedicine.com/medline/citation/17931419/Responses_of_cancer_cells_with_wild_type_or_tyrosine_kinase_domain_mutated_epidermal_growth_factor_receptor__EGFR__to_EGFR_targeted_therapy_are_linked_to_downregulation_of_hypoxia_inducible_factor_1alpha_ L2 - https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-6-63 DB - PRIME DP - Unbound Medicine ER -