aBETting therapeutic resistance by Wnt signaling

Engelke, Carl G.; Chinnaiyan, Arul M.

doi:10.1038/cr.2015.127

Cited by 10 publications

(8 citation statements)

References 11 publications

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“…The efficacy of several BET inhibitors is being tested in clinical trials in patients with hematological malignancies 12 , although it is unfortunate that the development of resistance to these drugs are expected. In this regard, two recent papers identifying the mechanism underlying therapeutic resistance in acute myeloid leukemia (AML) as elevated Myc expression due to high Wnt signals are intriguing 43 – 45 , given the present study demonstrating that AGN and decursin efficiently downregulate Myc levels. This result suggests that they may be used to overcome resistance to JQ1 in AML and further studies are necessary in order to validate this idea.…”

Section: Discussionmentioning

confidence: 70%

Angelica gigas Nakai and Decursin Downregulate Myc Expression to Promote Cell Death in B-cell Lymphoma

Kim

Nam

Chang

et al. 2018

Sci Rep

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Angelica gigas Nakai (AGN) is an oriental traditional medicine to treat anemia, dysmenorrhea, and migraine. However, its anti-lymphoma effect is yet to be tested. Here, we demonstrated that AGN and its major component decursin target Myc to suppress lymphomagenesis in vitro and in vivo. AGN inhibited cell viability in multiple B lymphoma cells, while sparing normal splenocytes and bone marrow cells. Increased cleaved PARP level and caspase 3/7 activity and the repression of survival-promoting AKT/mTOR and MAPK pathways downstream of BCR, were responsible for the pro-apoptotic effects of AGN. We found that Myc, a prominent downstream target of these signaling pathways, contributes to AGN-induced cell death. Moreover, co-treatment with AGN and a Myc inhibitor, JQ1 or 10058-F4 yielded synergistic cytotoxic activities against cancer cells with markedly reduced Myc expression. AGN downregulated Myc expression and suppressed tumorigenesis in Eμ-myc transgenic mice. The proapoptotic activities of AGN were recapitulated by decursin, indicating that the anti-tumor effect of AGN was mainly caused by decursin. These findings suggest that AGN and decursin possess potent anti-lymphoma activity, and combination therapies with AGN/decursin and a Myc inhibitor to target Myc more efficiently could be a valuable avenue to explore in the treatment of B-cell lymphoma.

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Section: Discussionmentioning

confidence: 70%

Angelica gigas Nakai and Decursin Downregulate Myc Expression to Promote Cell Death in B-cell Lymphoma

Kim

Nam

Chang

et al. 2018

Sci Rep

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“…4D, right). Thus, sulforaphane required the presence of CCAR2, and circumvented resistance mechanisms in JQ1-resistant colon cancer cells (39,40). Our working model (Fig.…”

Section: Ccar2 Acetylation Interferes With Wnt Coactivator Functionsmentioning

confidence: 91%

Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition

Rajendran¹,

Johnson²,

Li³

et al. 2019

Cancer Research

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There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and b-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphaneþJQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. Significance: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.

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“…We can expect similar resistance mechanisms for RAS antagonists. Similarly, in mouse models of BET inhibitor-resistant AML, activation of the WNT pathway was found to be the principal mediator of JQ1 resistance 49 . Again, similar mechanisms are likely to mediate resistance to MYC antagonists.…”

Section: What Are the Future Challenges For This Field Of Research?mentioning

confidence: 91%

Drugging the 'undruggable' cancer targets

et al. 2017

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The term ‘undruggable’ was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to ‘drug’ many of these targets, and therefore more appropriate terms might be ‘difficult to drug’ or ‘yet to be drugged’. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.

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aBETting therapeutic resistance by Wnt signaling

Cited by 10 publications

References 11 publications

Angelica gigas Nakai and Decursin Downregulate Myc Expression to Promote Cell Death in B-cell Lymphoma

Angelica gigas Nakai and Decursin Downregulate Myc Expression to Promote Cell Death in B-cell Lymphoma

Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition

Drugging the 'undruggable' cancer targets

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