Oncotarget

Research Papers:

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 Ó 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

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Oncotarget. 2019; 10:494-510. https://doi.org/10.18632/oncotarget.26563

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Abstract

Thomas J. Ow1,2,12, Cory D. Fulcher1, Carlos Thomas2, Pilib Ó Broin3, Andrea López4, Denis E. Reyna4, Richard V. Smith1,2,5,12, Catherine Sarta1, Michael B. Prystowsky2,12, Nicolas F. Schlecht2,6,7,8, Bradley A. Schiff1, Gregory Rosenblatt2, Thomas J. Belbin2,9, Thomas M. Harris2, Geoffrey C. Childs2, Nicole Kawachi2, Chandan Guha2,10,12 and Evripidis Gavathiotis4,11,12

1Department of Otorhinolaryngology-Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

2Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

3School of Mathematics, Statistics, and Applied Mathematics, National University of Ireland Galway, Galway, Ireland

4Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA

5Department of Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

6Department of Epidemiology & Population Health, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

7Department of Medicine (Oncology), Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

8Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

9Discipline of Oncology, Memorial University of Newfoundland, St. John’s, NL, Canada

10Department of Radiation Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

11Department of Medicine (Cardiology), Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA

12Albert Einstein Cancer Center, Bronx, NY, USA

Correspondence to:

Thomas J. Ow, email: thow@montefiore.org

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

Received: April 24, 2018    Accepted: December 16, 2018    Published: January 11, 2019

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.


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