The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic <i>BRAF</i> Mutant Colorectal Cancer

Forsythe, Nicholas; Refaat, Alaa; Javadi, Arman; Khawaja, Hajrah; Weir, Jessica; Emam, Heba; Allen, Wendy L.; Burkamp, Frank; Popovici, Vlad; Jithesh, Puthen V.; Isella, Claudio; LaBonte, Melissa J.; Mills, Ian G.; Johnston, Patrick G.; Schaeybroeck, Sandra Van

doi:10.1158/1535-7163.mct-17-0603

Cited by 20 publications

(28 citation statements)

References 53 publications

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“…In the presence of severe and irreparable ER stress, the UPR activates the intrinsic apoptosis pathway [27]. Several studies demonstrated that agents targeting ER stress and the UPR had antiproliferative effects in cancer cells [28–32], suggesting that affecting ER stress pathways may provide novel strategies for cancer therapy. Our results show that CWP232291 triggers ER stress.…”

Section: Discussionmentioning

confidence: 99%

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Pak

Park

Kim

et al. 2019

J Exp Clin Cancer Res

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Background Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/β-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule β-catenin inhibitor, were investigated in prostate cancer. Methods We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/β-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models. Results CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of β-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo. Conclusions Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule β-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/β-catenin signaling may be a novel strategy against CRPC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1342-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Pak

Park

Kim

et al. 2019

J Exp Clin Cancer Res

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“…The activation of ERK1/2 in response to calcium oscillations is multifaceted. Although ERK1/2 activity counteracts the damages induced by an acute increase in intracellular calcium [45], in colorectal cancer, the oncogenic activation of BRAF/MEK/ERK1/2 induces a chronic ER stress that promotes cell survival and is associated with tumor progression and poor patient outcome [92]. Under nutrients depletion, another condition inducing ER stress, ERK1/2 is activated by the autocrinely produced IL-4 in prostate, breast, ovarian, head, and neck cancers, and contributes to cell survival by activating the anti-apoptotic proteins survivins [93].…”

Section: Erks Favor the Adaptation To Environmental Stressesmentioning

confidence: 99%

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Salaroglio

Mungo

Gazzano

et al. 2019

IJMS

110

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The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is widely exploited by cancer cells subjected to environmental stresses, such as chemotherapy and anti-tumor activity of the host immune system. Aggressive tumors have a tremendous ability to adapt and survive in stressing and unfavorable conditions. The simultaneous resistance to chemotherapy and immune system responses is common, and ERK signaling plays a key role in both types of resistance. In this review, we dissect the main ERK-dependent mechanisms and feedback circuitries that simultaneously determine chemoresistance and immune-resistance/immune-escape in cancer cells. We discuss the pros and cons of targeting ERK signaling to induce chemo-immune-sensitization in refractory tumors.

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“…On the other hand, we expected that the activation of pro-apoptotic arms of the UPR may lead prostate cancer cells to cell death. To verify our hypothesis we tested a new compounds (ONC201) known to induce an integrated stress response ATF4-and CHOP-dependent in other cancer models and in phase I and II trials [2,30] (Figure 2 and Supplementary figure 1, a). For the first time, we observed an ONC201induced activation of all the arms of the UPR in the first 24hours.…”

Section: Discussionmentioning

confidence: 98%

“…Given that downregulation of CHOP led to cell survival, we hypothesized that the activation of pro-apoptotic arms of the UPR may enhance cell death. To achieve this, we utilized two different compounds (HA15 and ONC201) known to activate the UPR in other models [2,30].…”

Section: Chronic Activation Of the Unfolded Protein Response With Imimentioning

confidence: 99%

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Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201

Amoroso

Glass

Liberal

et al. 2019

Preprint

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Running Title: ONC201 can increase radiation response in prostate cancer. AbstractProstate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR -ATF4, ATF6 and IRE1-XBP1 -culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways.Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.

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The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer

Cited by 20 publications

References 53 publications

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201

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