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J Oral Pathol Med. 2018 Sep 30. doi: 10.1111/jop.12784. [Epub ahead of print]

JQ1 and PI3K inhibition synergistically reduce salivary adenoid cystic carcinoma malignancy by targeting the c-Myc and EGFR signaling pathways.

Author information

1
School of Stomatology, Shandong University, Jinan City, China.
2
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong university, Jinan City, China.
3
Department of Implantology Unit, Dongguan Dental Hospital, Dongguan City, China.
4
Department of Gynecology, Qilu Hospital, Jinan City, China.

Abstract

BACKGROUND:

To investigate the therapeutic mechanism of the BRD4 inhibitor JQ1 in SACC-83 cells and explore strategies to enhance its therapeutic potential.

MATERIAL AND METHODS:

SACC-83 cells were used in the experiment. Immunohistochemistry was used to assess BRD4 expression in SACC tissues and corresponding adjacent non-tumor tissues. Cell viability and proliferation were evaluated using the Cell Counting Kit-8 assay. Flow cytometry was used to quantitate apoptosis. Levels of cleaved caspase-3, BRD4, c-Myc, pEGFR (γ-1173), and EGFR were determined by quantitative real-time PCR and Western blot. To study the role of EGFR in JQ1 resistance, we generated EGFR knockdown SACC-83 cells by siRNA transfection.

RESULTS:

Our study revealed that BRD4 was overexpressed and could be a treatment target in SACC. The BRD4 inhibitor JQ1 markedly inhibited c-Myc expression in SACC-83 cells, which produced modest therapeutic effects. Nevertheless, the EGFR pathway was strongly activated following JQ1 treatment, which led to JQ1 resistance. Combined JQ1 and PI3K inhibitor treatment effectively increased the therapeutic potential by inhibiting the EGFR and c-Myc signaling pathways in SACC-83 cells. Moreover, EGFR knockdown sensitized SACC-83 cells to JQ1.

CONCLUSION:

These data demonstrate that EGFR and c-Myc signaling synergistically drive SACC progression. The JQ1 and PI3K inhibitor combination exhibited a strong synergistic effect by suppressing c-Myc and EGFR in SACC-83 cells, identifying a novel rational combinatorial treatment. Moreover, EGFR expression influences the sensitivity of SACC-83 cells to JQ1, which is useful for planning treatment.

KEYWORDS:

EGFR; JQ1; PI3K inhibitor; c-Myc; salivary adenoid cystic carcinoma

PMID:
30269363
DOI:
10.1111/jop.12784

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