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

Thomas J. Ow, Cory D. Fulcher, Carlos Thomas, Pilib Broin, Andrea López, Denis E. Reyna, Richard V. Smith, Catherine Sarta, Michael B. Prystowsky, Nicolas F. Schlecht, Bradley A. Schiff, Gregory Rosenblatt, Thomas J. Belbin, Thomas M. Harris, Geoffrey C. Childs, Nicole Kawachi, Chandan Guha, Evripidis Gavathiotis

Research output: Contribution to journalArticle

7 Scopus citations

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 prosurvival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells.

Original languageEnglish (US)
Pages (from-to)494-510
Number of pages17
JournalOncotarget
Volume10
Issue number4
StatePublished - Jan 1 2019

Keywords

  • A-1210477
  • BCL-xL
  • Head
  • MCL-1
  • Navitoclax
  • Neck squamous carcinoma

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Ow, T. J., Fulcher, C. D., Thomas, C., Broin, P., López, A., Reyna, D. E., Smith, R. V., Sarta, C., Prystowsky, M. B., Schlecht, N. F., Schiff, B. A., Rosenblatt, G., Belbin, T. J., Harris, T. M., Childs, G. C., Kawachi, N., Guha, C., & Gavathiotis, E. (2019). Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1. Oncotarget, 10(4), 494-510.