Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Lankes, Katharina; Hassan, Zonera; Doffo, María Josefina; Schneeweis, Christian; Lier, Svenja; Oellinger, Rupert; Rad, Roland; Kraemer, Oliver; Keller, Ulrich; Saur, Dieter; Reichert, Maximilian; Schneider, Günter; Wirth, Matthias

doi:10.1101/2020.07.01.182162

Cited by 8 publications

(20 citation statements)

References 80 publications

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“…In addition, the exon structure of the TFRC gene is depicted (black boxes). C A mRNA expression dataset of human PDAC were retrieved via the publication of Bailey et al [22] and curated as described [52]. A gene set enrichment analysis (GSEA) of Hallmark signatures via the GeneTrial 3.0 platform [110] was conducted comparing PDACs with TFRC mRNA expression in the highest quartile (Q4) versus PDACs in the quartiles Q1, Q2, and Q3.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, reduction in MYC expression increased paclitaxel-induced cell death in the resistant lines, whereas overexpression reduced paclitaxel-induced cell death in the parental PDAC cells [51]. Interestingly, gemcitabine was found to trigger a MYC-associated vulnerability in unbiased screening experiments [38,52,53] and deregulated MYC sensitizes to mitotic perturbants, including paclitaxel [54,55]. Such data highlight the need for further research on MYC-associated vulnerabilities and point to a specific context, exemplified here by lineage or secondary versus primary resistance, that needs to be understood.…”

Section: Drug Resistance and Mycmentioning

confidence: 99%

“…A drug screening of FDA approved anti-cancer drugs and analysis of several public repositories revealed an increased sensitivity toward perturbations of the protein homeostasis in MYC high PDAC cells [52]. MYC orchestrates a variety of biological processes by regulating and tuning the transcriptional and translational output [85].…”

Section: Targeting Myc-associated Vulnerabilitiesmentioning

confidence: 99%

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Rationale for MYC imaging and targeting in pancreatic cancer

et al. 2021

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The incidence and lethality of pancreatic ductal adenocarcinoma (PDAC) will continue to increase in the next decade. For most patients, chemotherapeutic combination therapies remain the standard of care. The development and successful implementation of precision oncology in other gastrointestinal tumor entities point to opportunities also for PDAC. Therefore, markers linked to specific therapeutic responses and important subgroups of the disease are needed. The MYC oncogene is a relevant driver in PDAC and is linked to drug resistance and sensitivity. Here, we update recent insights into MYC biology in PDAC, summarize the connections between MYC and drug responses, and point to an opportunity to image MYC non-invasively. In sum, we propose MYC-associated biology as a basis for the development of concepts for precision oncology in PDAC.

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Section: Discussionmentioning

confidence: 99%

Section: Drug Resistance and Mycmentioning

confidence: 99%

Section: Targeting Myc-associated Vulnerabilitiesmentioning

confidence: 99%

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Rationale for MYC imaging and targeting in pancreatic cancer

et al. 2021

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“…However, cancers with increased c-Myc activity display increased sensitivity to proteostasis stress. They are sensitive to proteasome inhibitors in pre-clinical models [75]. These drugs have not produced benefits in a clinical trial of metastatic pancreatic cancer enrolling unselected patients.…”

Section: Targeting P53: Therapeutic Avenues In Pancreatic Cancermentioning

confidence: 99%

Mutations of p53 associated with pancreatic cancer and therapeutic implications

Voutsadakis

2021

Ann Hepatobiliary Pancreat Surg

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Pancreatic adenocarcinoma is a malignancy with rising incidence and grim prognosis. Despite improvements in therapeutics for treating metastatic pancreatic cancer, this disease is invariably fatal with survival time less than a few years. New molecular understanding of the pathogenesis of pancreatic adenocarcinoma based on efforts led by The Cancer Genome Atlas and other groups has elucidated the landscape of this disease and started to produce therapeutic results, leading to the first introduction of targeted therapies for subsets of pancreatic cancers bearing specific molecular lesions such as BRCA mutations. These efforts have highlighted that subsets of pancreatic cancers are particularly sensitive to chemotherapy. The most common molecular lesions in pancreatic adenocarcinomas are mutations in an oncogene KRAS and the TP53 gene that encodes for tumor suppressor protein p53. This paper will review the landscape of pancreatic cancers, focusing on mutations of p53, a major tumor suppressor protein, in pancreatic cancers and possible therapeutic repercussions.

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“…Pro-apoptotic sensor proteins including NOXA, which directly binds to MCL1, neutralize the anti-apoptotic function of the protector proteins (10), leading to the initiation of apoptotic cell death. In PDAC, NOXA is tightly regulated at the transcriptional level, and transcriptional activation of NOXA by HDACinhibitors or proteasome inhibitors contribute to induce the cell intrinsic apoptosis pathway (11)(12)(13). Furthermore, NOXA is regulated by multiple transcription factors including p53 and is involved in apoptosis under genotoxic stress (14,15).…”

Section: Introductionmentioning

confidence: 99%

NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

Doffo

Bamopoulos

Köse

et al. 2021

Preprint

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Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The pro-apoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models we identified an inhibitor of the transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss of function experiments we validated that the mode of action depends on RUNX1 and NOXA. Of note, RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a novel way to target a therapy resistant PDAC, an unmet clinical need.

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Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Cited by 8 publications

References 80 publications

Rationale for MYC imaging and targeting in pancreatic cancer

Rationale for MYC imaging and targeting in pancreatic cancer

Mutations of p53 associated with pancreatic cancer and therapeutic implications

NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

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