Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck.
Squamous cell carcinoma of the head and neck (SCCHN) is a leading cause of cancer deaths worldwide. Epidermal growth factor receptor (EGFR), an upstream mediator of signal transducer and activator of transcription (STAT)-3 is overexpressed in a variety of cancers, including SCCHN. Therapies such as monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have demonstrated limited antitumor efficacy, which may be explained, in part, by persistent STAT3 activation despite EGFR inhibition. STAT3 activation induces expression of target genes in SCCHN, including Bcl-X(L), a mediator of antiapoptotic activity. Bcl-X(L) is commonly overexpressed in SCCHN where it correlates with chemoresistance, making it a potential therapeutic target. Targeting the EGFR-STAT3-Bcl-X(L) pathway at several levels, including the upstream receptor, the intracellular transcription factor, and the downstream target gene, has not been investigated previously. Using erlotinib, an EGFR-specific reversible tyrosine kinase inhibitor in combination with a STAT3 transcription factor decoy, we found enhanced antitumor effects in vitro and in vivo. The combination of the STAT3 decoy and gossypol, a small molecule targeting Bcl-X(L), also yielded enhanced inhibition of cell proliferation. The triple combination of erlotinib, STAT3 decoy, and gossypol further enhanced cell growth inhibition and apoptosis in vitro, and it down-regulated signaling molecules further downstream of the EGFR-STAT3 signaling pathway, such as cyclin D1. These results suggest that combined targeting of several components of an oncogenic signaling pathway may be an effective therapeutic strategy for SCCHN.
Boehm
Amanda L
AL
Department of Pathology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Sen
Malabika
M
Seethala
Raja
R
Gooding
William E
WE
Freilino
Maria
M
Wong
Silvia Man Yan
SM
Wang
Shaomeng
S
Johnson
Daniel E
DE
Grandis
Jennifer Rubin
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051020:bcl-X Protein; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors