Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck
الباحث الأول:
Carter RJ
الباحثين الآخرين:
Rachel J. Carter, Mateus Milani, Michael Butterworth, Nicholas Harper, Govindaraju Yedida, Georgia Greaves, Aoula Al-Zebeeby, Andrea L. Jorgensen, Andrew G. Schache, Janet M. Risk, Richard J. Shaw, Terry M. Jones, Joseph J. Sacco, Adam Hurlstone, Gerald M. Cohen & Shankar Varadarajan
المجلة:
Nature/Cell Death & Disease
تاريخ النشر:
None
مختصر البحث:
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
associate…
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.
