Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-XL, and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-XL and MCL-1, with little or no BCL-2. Although expression levels of BCL-XL and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-XL and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.
Highlights
Head and neck cancer, of which squamous cell carcinomas account for over 90% of diagnoses, is the sixth most common cancer worldwide[1]
Given the poorer clinical outcome associated with human papillomavirus (HPV)− SCCHN, we wished to explore the potential of BH3 mimetic therapy in this disease
Hematological malignancies largely depend on a single antiapoptotic member for survival, and as a result, monotherapy with BH3 mimetics has been successful[12,16,17]
Summary
Of which squamous cell carcinomas account for over 90% of diagnoses, is the sixth most common cancer worldwide[1]. Etiological factors, such as tobacco use, alcohol consumption, and human papillomavirus (HPV) infection, as well as the mutation of key genes associated with SCCHN have been identified, this has not translated into better therapies and the prognosis for many HPV negative (HPV−) patients remains significantly poorer than for HPV positive patients[2,3,4]. The only targeted therapy approved for SCCHN was the monoclonal antibody, cetuximab, which inhibits the epidermal growth factor receptor (EGFR). There is new promise for immunotherapy, with the recent FDA approval of the PD-1 specific antibody Pembrolizumab for first-line treatment of SCCHN7
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