%0 Journal Article
%T Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1
%A Andrea L¨®pez
%A Bradley A. Schiff
%A Carlos Thomas
%A Catherine Sarta
%A Chandan Guha
%A Cory D. Fulcher
%A Denis E. Reyna
%A Evripidis Gavathiotis
%A Geoffrey C. Childs
%A Gregory Rosenblatt
%A Michael B. Prystowsky
%A Nicolas F. Schlecht
%A Nicole Kawachi
%A Pilib ¨® Broin
%A Richard V. Smith
%A Thomas J. Belbin
%A Thomas J. Ow
%A Thomas M. Harris
%J Archive of "Oncotarget".
%D 2019
%R 10.18632/oncotarget.26563
%X 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 ¨C 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 8.9¦ÌM (range 6.6¦ÌM ¨C 13.9¦ÌM). 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 10.7¦ÌM (range, 8.8¦ÌM to 12.7¦ÌM). 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
%K head and neck squamous carcinoma
%K MCL-1
%K BCL-xL
%K navitoclax
%K A-1210477
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355180/