Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1

The cover for issue 4 of Oncotarget features Figure 6, "Bliss Independence analysis to evaluate synergistic activity between ABT-263 (navitoclax) and A-1210477," by Ow, et al.

The BCL-xL protein was expressed in 8 HNSCC cell lines examined.

MCL-1, a potential mediator of resistance to ABT-263, was expressed in all cell lines and HNSCC patient tumors, in addition to BCL-xL. This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family pro-survival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells.

"Head and neck squamous cell carcinoma is diagnosed in approximately 55,000 patients in the United States each year, and it is among the most common cancers worldwide."

Thus, one can surmise that many locoregional recurrences of HNSCC represent either re-growth of tumor cells that have survived cisplatin and/or radiation treatment or new malignant cells that have arisen within the treated field.

Figure 6: Bliss Independence analysis to evaluate synergistic activity between ABT-263 (navitoclax) and A-1210477. Cell viability curves and Bliss Independence analysis scores after treatment with ABT-263 (navitoclax) and A-1210477 across varying doses in PCI15B (A), Detroit 562 (B), MDA686LN (C), and HN30 (D).

Additionally, radiation and cytotoxic chemotherapy cause preferential tumor cell death via accumulation of fatal DNA damage, which can lead to apoptosis as one potential mechanism of tumor cell death.

This mechanism has been previously reported in HNSCC, and upregulation of BCL-2 has been shown to be associated with cisplatin resistance and poor outcome in oropharyngeal squamous cell carcinoma.

Anti-apoptotic proteins such as BCL-2, BCL-xL, and MCL-1 work in concert to inhibit apoptosis, the redundant role that these molecules play in HNSCC deserves further examination.

MCL-1 expression was associated with resistance to radiation in HNSCC cells and found to increase in expression after treatment with ABT-263.

"MCL-1 expression correlated with radiation resistance in HNSCC cells, and inhibition of MCL-1 with A-1210477 enhanced response to ABT-263."

Full text - https://doi.org/10.18632/oncotarget.26563

Correspondence to - Thomas J. Ow - [email protected]

Keywords - head and neck squamous carcinoma, MCL-1, BCL-xL, navitoclax, A-1210477