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 - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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Clinical significance and prospective molecular mechanism of C‑C motif chemokine receptors in patients with early‑stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy. Oncol Rep. 2019 Aug 13;: Authors: Zhou X, Liao X, Wang X, Huang K, Yang C, Yu T, Liu J, Han C, Zhu G, Su H, Qin W, Han Q, Liu Z, Huang J, Gong Y, Ye X, Peng T Abstract The present study aimed to determine the clinical significance and potential molecular mechanisms of C‑C motif chemokine receptor (CCR) genes in patients with early‑stage pancreatic ductal adenocarcinoma (PDAC). The transcriptomic, survival and clin...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
AbstractNab-paclitaxel plus gemcitabine (Nab-Gem) represents one of the standard regimen for first-line treatment of metastatic pancreatic adenocarcinoma (mPDAC). However, few data are available in mPDAC relapsed after gemcitabine as adjuvant treatment. Our study aims to evaluate the efficacy and feasibility of Nab-Gem as first-line treatment for mPDAC patients previously treated with adjuvant treatment. We retrospectively analyzed the safety and efficacy data of 36 patients, who received first-line Nab-Gem after gemcitabine as adjuvant treatment. All patients received gemcitabine after radical surgery. Median disease-free...
Source: Medical Oncology - Category: Cancer & Oncology Source Type: research
Contributors : W Zhang ; J Wang ; B Chiu ; L Hou ; Z Zhang ; C ZengSeries Type : Methylation profiling by arrayOrganism : Homo sapiensGenome wide DNA hydroxymethylation profiling of tumor and adjacent tissue samples in pancreatic cancer. The Illumina Infinium MethylationEPIC BeadChip was used to obtain DNA hydroxymethylation profiles across approximately 850,000 CpGs in paired tumor and tumor adjacent tissues in 17 adult patients with primary pancreatic adenocarcionoma .
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by array Homo sapiens Source Type: research
In this study, the expression profiles of circRNAs from 10 PDAC tissues and their paired adjacent nontumor tissues were analyzed through RNA sequencing analysis. An enrichment analysis was employed to predict the functions of the differentially expressed circRNAs. Sequence alignment information and mRNA microarray projects were used to predict the RNA regulatory network. The knockdown of circRNAs by small interfering RNAs followed by wound healing and western blot assays was used to confirm their functions in a PDAC cell line. A total of 278 circRNAs were identified as differentially expressed in PDAC tissue. Of these, we ...
Source: Journal of Oncology - Category: Cancer & Oncology Tags: J Oncol Source Type: research
Publication date: 20 August 2019Source: Cell Reports, Volume 28, Issue 8Author(s): Adam L. Burrack, Ellen J. Spartz, Jackson F. Raynor, Iris Wang, Margaret Olson, Ingunn M. StromnesSummaryPancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhance...
Source: Cell Reports - Category: Cytology Source Type: research
In the era of skyrocketing health care costs, measuring value in the hospital setting has become crucial. Pancreatic cancer, a notoriously aggressive disease with complex management, has in recent years been aggregated to specialized medical centers. In this issue of JAMA Surgery, Bateni et al present a review of outcomes and cost after attempted curative resection for early-stage pancreatic adenocarcinoma. Data were obtained from the California Cancer Registry along with the Office of Statewide Hospital Planning and Development. Consistent with previous reports, the study showed that high-volume and National Cancer Instit...
Source: JAMA Surgery - Category: Sports Medicine Source Type: research
This article is protected by copyright. All rights reserved. PMID: 31432501 [PubMed - as supplied by publisher]
Source: Clinical Genetics - Category: Genetics & Stem Cells Authors: Tags: Clin Genet Source Type: research
The importance of peritoneal washing cytology status both as a sign of irresectability and as a prognostic factor for pancreatic ductal adenocarcinoma remains controversial. The purpose of this nationwide, cancer registry –based study was to clarify the clinical implications of operative resection in patients who had positive cytology status.
Source: Surgery - Category: Surgery Authors: Source Type: research
Conclusions The present propensity-matched analysis showed a significant association with survival for earlier delivery of chemotherapy in the adjuvant setting.
Source: Pancreas - Category: Gastroenterology Tags: Original Articles Source Type: research
Conclusions In tumor cells, MCT1 expression is associated with better prognosis and reduced nodal metastasis in pancreatic cancer, contrary to findings of past in vitro studies. Conversely, MCT4 expression in CAFs is indicative of worse prognosis.
Source: Pancreas - Category: Gastroenterology Tags: Original Articles Source Type: research
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