NSCLC Driven by <i>DDR2</i> Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy

Xu, Chunxiao; Buczkowski, Kevin A.; Zhang, Yanxi; Asahina, Hajime; Beauchamp, Ellen M.; Terai, Hideki; Li, Yvonne Y.; Meyerson, Matthew; Wong, Kwok-Kin; Hammerman, Peter S.

doi:10.1158/1535-7163.mct-15-0077

Cited by 29 publications

(33 citation statements)

References 36 publications

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“…JQ1, a firstin-class small-molecule inhibitor of BRD4, engages to competitively bind to the acetyl-lysine recognition area of BRD4, displaces BRD4 from acetylated chromatin, and represses transcription of targeted genes in the influenced chromatin region. The specific BET inhibitors have demonstrated apparent efficacy in blocking tumor progression in a range of cancer models including castration-resistant prostate cancer (29), acute myeloid leukemia (30), melanoma (20), multiple myeloma (31), and lung carcinoma (32)(33)(34). Nevertheless, the role of BRD4 in bladder cancer progression and the therapeutic effect of BRD4 inhibitor in treatment of bladder cancer are still unknown.…”

Section: Discussionmentioning

confidence: 99%

BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer

Liu

Tang

et al. 2016

Molecular Cancer Therapeutics

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People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo. We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC. In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease.

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Section: Discussionmentioning

confidence: 99%

BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer

Liu

Tang

et al. 2016

Molecular Cancer Therapeutics

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“…The reasons for the development of resistance from target therapy are not entirely clear. However, the possibility exists that BET inhibitors in combination with target therapy agents could overcome the resistance in thyroid cancer as shown for metastatic breast cancer (46, 47), for metastatic melanoma (48) and lung cancer (49). Thus, the present studies have raised new possibility for the effective treatment modalities for poorly differentiated and undifferentiated thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

Zhu

Enomoto

Zhao

et al. 2017

Clinical Cancer Research

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Purpose New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent anti-tumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined anti-tumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. Experimental Design We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer.

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“…Although we cannot rule out a chance effect, our LTR patients appeared to have an accumulation of rare mutations, including BRAF , KEAP1 , and DDR2 . Many of these mutations are at the same time prognostic markers, and targets for molecular therapy [7,9,42,43,44,45]. Despite earlier assumptions, EGFR mutations themselves were not prognostic in a recent meta-analysis [46].…”

Section: Discussionmentioning

confidence: 99%

Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy

Gautschi

Stadelmann²,

Aebersold-Keller³

et al. 2015

Oncol Res Treat

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Background: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. Patients and Methods: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR. Results: Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC. Conclusion: Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC.

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NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy

Cited by 29 publications

References 36 publications

BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer

BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy

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