American Association for Cancer Research
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00085472can180459-sup-196968_2_supp_4756995_p8qdk4.pdf (189.54 kB)

Suppl Figure 7 from BET Inhibition Overcomes Receptor Tyrosine Kinase–Mediated Cetuximab Resistance in HNSCC

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journal contribution
posted on 2023-03-31, 01:41 authored by Brandon Leonard, Toni M. Brand, Rachel A. O'Keefe, Eliot D. Lee, Yan Zeng, Jacquelyn D. Kemmer, Hua Li, Jennifer R. Grandis, Neil E. Bhola

Evaluation of RTK and Ki67 expression in PDX6282 treated with cetuximab and JQ1

Funding

NIH

American Cancer Society Post-Doctoral fellowship

American Cancer Society

Brandon Gromada Head and Neck Foundation

History

ARTICLE ABSTRACT

Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC.Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg. Cancer Res; 78(15); 4331–43. ©2018 AACR.