A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer

Dietlein, Felix; Kalb, Bastian; Jokić, Mladen; Noll, Elisa M.; Strong, Alexander; Tharun, Lars; Ozretić, Luka; Künstlinger, Helen; Kambartel, Kato; Randerath, Winfried; Jungreuthmayer, Christian; Schmitt, Anna; Torgovnick, Alessandro; Richters, André; Rauh, Daniel; Siedek, Florian; Persigehl, Thorsten; Mauch, Cornelia; Bártková, Jiřina; Bradley, Allan; Sprick, Martin R.; Trumpp, Andreas; Rad, Roland; Saur, Dieter; Bártek, Jiří; Wolf, Jürgen; Büttner, Reinhard; Thomas, Roman K.; Reinhardt, Hans Christian

doi:10.1016/j.cell.2015.08.017

Cited by 33 publications

(46 citation statements)

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“…MK2 inhibition may also be a potential target for combination therapies. Although we showed MK2 inhibition does not directly induce tumor cell apoptosis, inhibiting both MK2 along with the cell cycle promoter Chk1 results in tumor cytotoxicity across multiple therapy‐resistant cell lines . In a model of non‐small‐cell lung cancer, MK2 inhibition sensitized p53‐deficient tumors to cisplatin treatment .…”

Section: Discussionmentioning

confidence: 65%

“…MK2 may have a significant effect on one or more of these areas within CRC so further investigation is warranted. MK2 also participates in cell cycle/proliferation pathways, which may support its importance in survival and therefore could be a potential therapeutic target of interest . In glioblastoma cells, MK2 activity regulates the protumor protein Khsrp and induces secretion of IL‐6, which promotes tumor growth and invasion in glioblastoma .…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Ray

Berggren

Cruz

et al. 2017

Intl Journal of Cancer

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Colorectal cancer (CRC) development and progression is associated with chronic inflammation. We have identified the MAPK-activated protein kinase 2 (MK2) pathway as a primary mediator of inflammation in CRC. MK2 signaling promotes production of proinflammatory cytokines IL-1β, IL-6 and TNF-α. These cytokines have been implicated in tumor growth, invasion and metastasis. For the first time, we investigate whether MK2 inhibition can improve outcome in two mouse models of CRC. In our azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated CRC, MK2 inhibitor treatment eliminated murine tumor development. Using the implanted, syngeneic murine CRC cell line CT26, we observe significant tumor volume reduction following MK2 inhibition. Tumor cells treated with MK2 inhibitors produced 80% less IL-1β, IL-6 and TNF-α and demonstrated decreased invasion. Replenishment of downstream proinflammatory MK2-mediated cytokines (IL-1β, IL-6 and TNF-α) to tumors led to restoration of tumor proliferation and rapid tumor regrowth. These results demonstrate the importance of MK2 in driving proinflammatory cytokine production, its relevance to in vivo tumor proliferation and invasion. Inhibition of MK2 may represent an attractive therapeutic target to suppress tumor growth and progression in patients.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Ray

Berggren

Cruz

et al. 2017

Intl Journal of Cancer

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“…Interestingly, this effect was observed in cells that harbored KRAS mutations, a subset of CRCs particularly difficult to target and treat (Manic et al ., ). An independent study also observed efficacy of CHK1 inhibition in KRAS‐ mutated lung and colon adenocarcinoma cells, especially when combined with MK2 inhibitors (Dietlein et al ., ). MK2 functions in a pathway parallel to CHK1 and is responsible for maintaining cell cycle checkpoints in response to stress (Reinhardt et al ., ).…”

Section: Alternative Dna Repair‐targeting Therapies For Use In Colorementioning

confidence: 97%

“…MK2 functions in a pathway parallel to CHK1 and is responsible for maintaining cell cycle checkpoints in response to stress (Reinhardt et al ., ). KRAS ‐mutated cells exhibit intrinsic genotoxic stress that leads to constant activation of CHK1 and MK2, and inhibition of these proteins induced mitotic catastrophe in vitro , in murine cancer models, and in patient‐derived cells (Dietlein et al ., ). CHK1 inhibitors might be tested in KRAS ‐mutated CRC, a subset that currently has limited therapy options.…”

Section: Alternative Dna Repair‐targeting Therapies For Use In Colorementioning

confidence: 99%

Exploiting DNA repair defects in colorectal cancer

et al. 2019

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Colorectal cancer ( CRC ) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC . At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRC s. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma ( TCGA ‐ COAD ) and Rectal Adenocarcinoma ( TCGA ‐ READ ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly( ADP )‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA 1 and/or BRCA 2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA 1/ BRCA 2 mutations but exhibiting BRCA ‐ like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK 1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRC s to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.

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“…Lastly, almost all ABC‐DLBCLs display BCL2 amplification/overexpression , suggesting that BCL2 inhibitors, such as venetoclax, which displays remarkable activity in CLL , should be evaluated in ABC‐DLBCL both as single agents, but particularly in combination with agents targeting chronic active BCR signaling (BTK‐, PI3Kδ‐, SYK‐ and PKC‐ β inhibitors), the CBM complex (MALT1 inhibitors), the Myddosome (IRAK4 inhibitors), and JAK/STAT3 signaling. When designing experiments to address potential synergistic drug interactions, appropriate additivity models should be carefully chosen . Overall, there is a large and mostly unchartered space for the use of novel, targeted drugs in ABC‐DLBCL, which should be systematically explored using novel, autochthonous mouse models and carefully stratified clinical trials.…”

Section: Therapeutic Implications Derived From Genomic Insights In Abmentioning

confidence: 99%

Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma

Knittel

Liedgens

Korovkina

et al. 2016

European J of Haematology

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B-cell-like phenotype (GCB) and an activated B-cell-like phenotype (ABC). Particularly ABC-DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo-immune therapy. Through the availability of novel experimental technologies, such as next-generation sequencing and cutting-edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC-DLBCL. Currently, a picture is emerging which suggests that ABC-DLBCL critically depends on sustained activity of the NFjB pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B-, CARD11-, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC-DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non-physiological NFjB activity and repressing anti-apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials.

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A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer

Cited by 33 publications

References 0 publications

Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Exploiting DNA repair defects in colorectal cancer

Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma

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