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Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors


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The cover for issue 83 of Oncotarget features Figure 4, "Trametinib and the combined treatment of JQ1 and trametinib inhibit ATC cell migration," by Zhu, et al.

Combined treatment suppressed MYC expression more than single treatment, resulting in decreased expression of pro-survival regulators and increased pro-apoptotic regulators to collaboratively induce apoptosis.

In xenograft studies, single treatment only partially inhibited tumor growth, but the combined treatment inhibited tumor growth by >90%. Combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment.

Dr. Sheue-yann Cheng from the Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA "Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies"

Figure 4: Trametinib and the combined treatment of JQ1 and trametinib inhibit ATC cell migration. Monolayer scratch-induced migration assay. (A-I) THJ-11T cells or (B-I) THJ-16T cells treated with vehicle, JQ1, trametinib or combined JQ1 and trametinib were scratched with a 20-μl plastic pipette tip at 0 h and 24 h. (A-II) Quantitative analysis of wound-induced migration assay from (A-I). (B-II) Quantitative analysis of wound-induced migration assay from (B-I). The results are presented as mean ± SD of measurements of areas from six wells for each group.

MYC protein abundance was highly elevated in ATC tumors and the increased MYC expression was associated with unfavorable prognosis. JQ1 was shown to decrease MYC expression, arrest cell cycle progression, and suppress tumor growth in vivo. Further, JQ1 treatment significantly prolonged survival, inhibited tumor growth, and attenuated transcriptional programs critical for tumor cell proliferation .

However, intriguingly, we found that the effect of JQ1 was limited to the inhibition of tumor growth, and had no effect on tumor cell invasion and metastasis. MYC protein abundance in cells treated with double treatment was synergistically lower than with either single agent, leading to an enhanced inhibitory effect on tumor cell proliferation, tumor growth, and tumor cell invasion.

The Sheue-yann Cheng research team concluded, "THJ-11T cells express KRASG12V mutation, whereas THJ-16T cells express PI3KE454K, TP53, and RB mutations. Interestingly, the THJ-16T cells with mutations in PI3KE454K, TP53, and RB proliferated more slowly than the THJ-11T cells that had only KRASG12V mutation. Consistently, the development of xenograft tumors was also slower to reach 200 mm3 for THJ-16T cells than THJ-11T cells. In support of this notion, recent global genomic analyses have demonstrated that in ATC, in addition to mutations in TERT promoter, TP53, PI3K/AKT/mTOR pathway effectors, mutations in SWI/SNF subunits, histone methyltransferases, and EIF1AX were also detected."

Full text - https://doi.org/10.18632/oncotarget.26253

Correspondence to - Sheue-yann Cheng - chengs@mail.nih.gov

Keywords - tumorigenesis, anaplastic thyroid cancer, bromodomain and extraterminal protein inhibitor, JQ1, trametinib



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