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 J. Childs, Nicole Kawachi, Chandan Guha, Evripidis Gavathiotis

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Proteins
Cell Line
Inhibitory Concentration 50
Tissue Banks
Therapeutics
Radiation Dosage
Squamous Cell Neoplasms
Neoplasms
navitoclax
Carcinoma, squamous cell of head and neck
Inhibition (Psychology)
Discriminant Analysis
Head and Neck Neoplasms
Least-Squares Analysis
Cisplatin
Genes
Gene Expression
Recurrence

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1. / Ow, Thomas J.; Fulcher, Cory D.; Thomas, Carlos; Broin, Pilib; López, Andrea; Reyna, Denis E.; Smith, Richard V.; Sarta, Catherine; Prystowsky, Michael B.; Schlecht, Nicolas F.; Schiff, Bradley A.; Rosenblatt, Gregory; Belbin, Thomas J.; Harris, Thomas M.; Childs, Geoffrey J.; Kawachi, Nicole; Guha, Chandan; Gavathiotis, Evripidis.

In: Oncotarget, Vol. 10, No. 4, 01.01.2019, p. 494-510.

Research output: Contribution to journalArticle

Ow, TJ, Fulcher, CD, Thomas, C, Broin, P, López, A, Reyna, DE, Smith, RV, Sarta, C, Prystowsky, MB, Schlecht, NF, Schiff, BA, Rosenblatt, G, Belbin, TJ, Harris, TM, Childs, GJ, 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, vol. 10, no. 4, pp. 494-510.
Ow, Thomas J. ; Fulcher, Cory D. ; Thomas, Carlos ; Broin, Pilib ; López, Andrea ; Reyna, Denis E. ; Smith, Richard V. ; Sarta, Catherine ; Prystowsky, Michael B. ; Schlecht, Nicolas F. ; Schiff, Bradley A. ; Rosenblatt, Gregory ; Belbin, Thomas J. ; Harris, Thomas M. ; Childs, Geoffrey J. ; Kawachi, Nicole ; Guha, Chandan ; Gavathiotis, Evripidis. / Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1. In: Oncotarget. 2019 ; Vol. 10, No. 4. pp. 494-510.
@article{ef5648b23c624a098f0db96a19978281,
title = "Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1",
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.",
keywords = "A-1210477, BCL-xL, Head, MCL-1, Navitoclax, Neck squamous carcinoma",
author = "Ow, {Thomas J.} and Fulcher, {Cory D.} and Carlos Thomas and Pilib Broin and Andrea L{\'o}pez and Reyna, {Denis E.} and Smith, {Richard V.} and Catherine Sarta and Prystowsky, {Michael B.} and Schlecht, {Nicolas F.} and Schiff, {Bradley A.} and Gregory Rosenblatt and Belbin, {Thomas J.} and Harris, {Thomas M.} and Childs, {Geoffrey J.} and Nicole Kawachi and Chandan Guha and Evripidis Gavathiotis",
year = "2019",
month = "1",
day = "1",
language = "English (US)",
volume = "10",
pages = "494--510",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "4",

}

TY - JOUR

T1 - Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1

AU - Ow, Thomas J.

AU - Fulcher, Cory D.

AU - Thomas, Carlos

AU - Broin, Pilib

AU - López, Andrea

AU - Reyna, Denis E.

AU - Smith, Richard V.

AU - Sarta, Catherine

AU - Prystowsky, Michael B.

AU - Schlecht, Nicolas F.

AU - Schiff, Bradley A.

AU - Rosenblatt, Gregory

AU - Belbin, Thomas J.

AU - Harris, Thomas M.

AU - Childs, Geoffrey J.

AU - Kawachi, Nicole

AU - Guha, Chandan

AU - Gavathiotis, Evripidis

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - A-1210477

KW - BCL-xL

KW - Head

KW - MCL-1

KW - Navitoclax

KW - Neck squamous carcinoma

UR - http://www.scopus.com/inward/record.url?scp=85059878874&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059878874&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:85059878874

VL - 10

SP - 494

EP - 510

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 4

ER -