Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer


Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adenocarcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of>800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage-dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser62. Our study thus not only identifies a potential therapeutic target for patients with KRAS-mutant PDAC but also presents the application of a screening strategy that can be more broadly adapted to identify regulators of protein stability.

Source: Signal Transduction Knowledge Environment – July 16, 2019 Category: Science Authors: Blake, D. R., Vaseva, A. V., Hodge, R. G., Kline, M. P., Gilbert, T. S. K., Tyagi, V., Huang, D., Whiten, G. C., Larson, J. E., Wang, X., Pearce, K. H., Herring, L. E., Graves, L. M., Frye, S. V., Emanuele, M. J., Cox, A. D., Der, C. J. Tags: STKE Research Articles Source Type: news

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Source: Cancers – August 2, 2019 Category: Cancer & Oncology Authors: Asfar S. Azmi Yiwei Li Amro Aboukameel Irfana Muqbil Philip A. Philip Ramzi M. Mohammad Tags: Article Source Type: research

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Source: BMC Cancer – August 1, 2019 Category: Cancer & Oncology Authors: Ke Sun, Wei Li, Jun Han and Hong Wu Tags: Research article Source Type: research

Fausto Petrelli

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Source: Cancers – August 1, 2019 Category: Cancer & Oncology Authors: Michele Ghidini Angelica Petrillo Massimiliano Salati Shelize Khakoo Antonio Varricchio Gianluca Tomasello Francesco Grossi Fausto Petrelli Tags: Review Source Type: research

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Source: Cancers – July 28, 2019 Category: Cancer & Oncology Authors: Chen Macarulla Blanc Mirakhur Jong Belanger Bekaii-Saab Siveke Tags: Article Source Type: research

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Source: Briefings in Bioinformatics – July 27, 2019 Category: Bioinformatics Authors: Li M, Zhao J, Li X, Chen Y, Feng C, Qian F, Liu Y, Zhang J, He J, Ai B, Ning Z, Liu W, Bai X, Han X, Wu Z, Xu X, Tang Z, Pan Q, Xu L, Li C, Wang Q, Li E Tags: Brief Bioinform Source Type: research

ConclusionSurgical treatment should be considered for pancreatic metastasis from lung cancer if the disease is localized and the patient’s condition is good. Additionally, combined therapy, including surgical resection, may be effective for repeated recurrence.

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