Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck

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.

ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma

“…To explore whether endogenous ANO1 expression correlates with the levels of selected proteins involved in mitochondrial apoptotic pathway, we studied by immunoblotting their expression patterns in five UT-SCC and two GIST cell lines with high ANO1 expression (UT-SCC-8, UT-SCC-14, UT-SCC-87, GIST48, GIST-T1), as well as two UT-SCC cell lines with low ANO1 expression (UT-SCC-11 and UT-SCC-95). MCL1 and BCL-XL were highly expressed in all the immunoblotted UT-SCC cell lines, supporting recent findings [ 33 ]. Interestingly, strong BCL2-b expression was observed in GIST cell lines ( Figure S3C ) but was almost undetectable in UT-SCC cell lines.…”

“…Interestingly, strong BCL2-b expression was observed in GIST cell lines ( Figure S3C ) but was almost undetectable in UT-SCC cell lines. In line with these findings, recent studies show dependency of HNSCC cells on both MCL1 and BCL-XL expression for survival, with little or no contribution from BCL2 [ 33 , 50 , 51 ].…”

“…Myeloid cell leukemia-1 gene ( MCL-1 ), encodes for MCL1, a BCL2 family member with crucial role in the regulation of apoptosis and cell cycle progression [ 31 ]. Cancer cells, including HNSCC, may hijack these processes by overexpressing MCL1, and thus promote cell survival [ 32 , 33 ]. Besides sharing many functional and structural similarities with other BCL2-family pro-survival proteins, MCL1 exhibits unique BH3-binding properties, a short protein half-life [ 34 ], and the ability to regulate mitochondrial metabolism [ 35 ].…”

The BCL-2 selective inhibitor ABT-199 sensitizes soft tissue sarcomas to proteasome inhibition by a concerted mechanism requiring BAX and NOXA

“…In general, the combination of specific BCL-2 inhibitors with other approved anti-cancer drugs repeatedly proved a successful strategy in various tumor models 56,57 ). The data presented here suggests that BCL-2 inhibition by BH3-mimetics is also a valid option for the treatment of solid tumors, especially in combination with established and effective drugs 56,[58][59][60][61][62] .…”

Ex Vivo Culture Models to Indicate Therapy Response in Head and Neck Squamous Cell Carcinoma

“…Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4409/9/11/2527/s1, Supplementary File S1: Search strategy for the PubMed and EMBASE databases; Table S1: Overview of included studies describing ex vivo culture models of HNSCC for chemotherapy and radiotherapy sensitivity testing; Table S2: Overview of included studies describing ex vivo culture models of HNSCC for immunotherapy and targeted therapy sensitivity testing. References [108][109][110][111][112][113][114][115][116][117][118][119][120] are cited in supplementary Tables S1 and S2.…”