Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy

Lipner, Matthew B.; Peng, Xianlu L.; Jin, Chong; Xu, Yi; Gao, Yanzhe; East, Michael P.; Rashid, Naim U.; Moffitt, Richard A.; Loeza, Silvia G. Herrera; Morrison, Ashley B.; Golitz, Brian T.; Vaziri, Cyrus; Graves, Lee M.; Johnson, Gary L.; Yeh, Jen Jen

doi:10.1172/jci.insight.129905

Cited by 33 publications

(17 citation statements)

References 66 publications

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“…Recent studies based on PDAC cell line based xenograft models have validated pharmacological inhibitors against targets associated with different oncogenic pathways, including EGFR-STAT3 signaling [98], YAP-TAZ pathway [96], KRAS signaling [99], CDK4/6 [100], SUMO pathway [101], and metabolic pathways [97,102]. Mechanistically, anti-tumor efficacies of these pharmacological inhibitors have been reported either direct or through chemosensitization [103,104]. Among other recent developments, using PANC-1 xenograft tumors, it has been demonstrated that iExosomes loaded with siRNA or shRNA targeting KRAS G12D suppressed the growth of orthotopic tumors of the pancreas [105].…”

Section: Experimental Models For Pancreatic Cancermentioning

confidence: 99%

Modeling pancreatic cancer in mice for experimental therapeutics

Mallya

Gautam

Aithal

et al. 2021

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Section: Experimental Models For Pancreatic Cancermentioning

confidence: 99%

Modeling pancreatic cancer in mice for experimental therapeutics

Mallya

Gautam

Aithal

et al. 2021

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…DMSO was used as the vehicle control at a concentration of 0.1% on cells. Synergistic effects of EpiKin176 with the combination therapy FOLFOX were assessed previously Lipner et al (2020), while this work focuses on a subset of this previous work. Seventy-two hours post-treatment, cells were lysed with CellTiter-Glo (Promega) per the manufacturer's protocol.…”

Section: Drug Screenmentioning

confidence: 99%

Kinome state is predictive of cell viability in pancreatic cancer tumor and stroma cell lines

Berginski

Jenner

Joisa

et al. 2021

Preprint

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Numerous aspects of cellular signaling are regulated by the kinome - the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation being a key driver of many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tissue microenvironment. Fundamentally, it is an open question as to the degree to which knowledge of the state of the kinome at the protein level is able to provide insight into the downstream phenotype of the cell. In this work, we attempt to link the state of the kinome, or kinotype, with cell viability in representative PDAC tumor and stroma cell lines. Through the application of both regression and classification models to independent kinome perturbation and kinase inhibitor cell screen data, we find that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. While regression models perform poorly, we find that classification approaches are able to predict drug viability effects. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines. These results suggest that characterizing the state of the protein kinome provides significant opportunity for better understanding signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapy design for PDAC.

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“…Compound screening was performed as previously described (Bevill et al, 2019;Lipner et al, 2020). Briefly, drug screening was performed in a 384 well plate format, in duplicate.…”

Section: Rtki Drug Screenmentioning

confidence: 99%

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Musicant

Parag-Sharma

Gong

et al. 2020

Preprint

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Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1a splice variant PGC-1a4, which regulates PPARg-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARg inhibition with inverse agonists.These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

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Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy

Cited by 33 publications

References 66 publications

Modeling pancreatic cancer in mice for experimental therapeutics

Modeling pancreatic cancer in mice for experimental therapeutics

Kinome state is predictive of cell viability in pancreatic cancer tumor and stroma cell lines

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

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