Abstract
Mechanisms of treatment resistance in head and neck squamous cell carcinoma (HNSCC) are not well characterized. In this study, HNSCC tumors from a cohort of prospectively enrolled subjects on an ongoing tissue banking study were divided into those that persisted or recurred locoregionally (n=23) and those that responded without recurrence (n=35). Gene expression was evaluated using llumina HumanHT-12-v3 Expression BeadChip microarrays. Sparse Partial Least Squares – Discriminant Analysis (sPLS-DA) identified 135 genes discriminating treatment-resistant from treatment-sensitive tumors. BCL-xL was identified among 23% of canonical pathways derived from this set of genes using Ingenuity Pathway analysis. The BCL-xL protein was expressed in 8 HNSCC cell lines examined. Cells were treated with the BCL-xL inhibitor, ABT-263 (navitoclax): the average half maximal inhibitory concentration (IC50) was 8.9μM (range 6.6μM – 13.9μM). Combining ABT-263 did not significantly increase responses to 2 Gy radiation or cisplatin in the majority of cell lines. 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. Treatment with the MCL-1 inhibitor, A-1210477, in HNSCC cell lines showed an average IC50 of 10.7μM (range, 8.8μM to 12.7μM). Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines. Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis. 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in approximately 55,000 patients in the United States each year [1], and it is among the most common cancers worldwide [2]
This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family prosurvival molecules in head and neck squamous cell carcinoma (HNSCC), and co-inhibition is synergistic in HNSCC cancer cells
A cohort of patients with HNSCC were selected for the study based on the inclusion and exclusion criteria described in the methods section
Summary
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in approximately 55,000 patients in the United States each year [1], and it is among the most common cancers worldwide [2]. Treatment recommendations for patients with HNSCC are selected based on disease site, clinical stage, and the morbidity associated with different treatment options. 50% of patients with HNSCC present with American Joint Committee on Cancer (AJCC) stage III or IV disease [3,4,5], and the vast majority of these patients receive radiation or combination cisplatin-radiation as either first-line or adjuvant therapy [6, 7]. 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. Little is known about the molecular factors that contribute most significantly to treatment failure in HNSCC
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