Heterozygous mutations in <i>p97</i> and resistance to p97 inhibitors

Bastola, Prabhakar; Minn, Kay; Chien, Jeremy

doi:10.1101/380964

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…Consistent with other compounds in its class, CB-5083 treatment showed a dose-dependent cytotoxicity ( Figure 1 A) with half-maximal growth inhibition (GI 50 ) ranging from 0.46 ± 0.07 μM to 0.94 ± 0.23 μM ( Figure 1 B). These GI 50 values are comparable to previously reported half-maximal growth inhibition values in the lung carcinoma cell line A459, the colon carcinoma cell line HCT116 [ 15 , 28 ], and patient-derived organoid models for ovarian cancer [ 29 ]. Our results suggest that CB-5083 can effectively inhibit in vitro cell growth in high-grade serous and clear cell ovarian cancer.…”

Section: Resultssupporting

confidence: 87%

Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer

Bastola

Leiserowitz

Chien

2022

Cancers

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Protein quality control mechanisms play an important role in cancer progression by providing adaptive responses and morphologic stability against genome-wide copy number alterations, aneuploidy, and conformation-altering somatic mutations. This dependency on protein quality control mechanisms creates a vulnerability that may be exploited for therapeutic benefits by targeting components of the protein quality control mechanism. Recently, valosin-containing protein (VCP), also known at p97 AAA-ATPase, has emerged as a druggable target in cancer cells to affect their dependency on protein quality control. Here, we show that VCP inhibitors induce cytotoxicity in several ovarian cancer cell lines and these compounds act synergistically with mifepristone, a drug previously shown to induce an atypical unfolded protein response. Although mifepristone at a clinically achievable dose induces a weak unfolded protein response, it enhances the cytotoxic effects of VCP inhibitor CB-5083. Mechanistically, mifepristone blocks the cytoprotective effect of ATF6 in response to endoplasmic reticulum (ER) stress while activating the cytotoxic effects of ATF4 and CHOP through the HRI (EIF2AK1)-mediated signal transduction pathway. In contrast, CB-5083 activates ATF4 and CHOP through the PERK (EIF2AK3)-mediated signaling pathway. This combination activates ATF4 and CHOP while blocking the adaptive response provided by ATF6, resulting in increased cytotoxic effects and synergistic drug interaction.

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Section: Resultssupporting

confidence: 87%

Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer

Bastola

Leiserowitz

Chien

2022

Cancers

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“…CB-5083, the first-in-class inhibitor of VCP, was shown to be effective in inhibiting tumour growth in preclinical models (62). Clinical trials of CB-5083 for solid and haematological malignancies however were recently prematurely terminated due to off-target effects on PDE6 resulting in ocular dysfunction (63). To circumvent potential issues of toxicity we evaluated alternative drugs to enhance radioiodine uptake, of which two of them -ebastine and clotrimazole -are well tolerated in vivo and FDA-approved (55).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologically targeting a novel pathway of sodium iodide symporter trafficking to enhance radioiodine uptake

Fletcher

Read

Thornton

et al. 2019

Preprint

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† Senior authors One Sentence Summary:Novel NIS interactors ARF4 and VCP alter NIS trafficking in vitro, and FDA-approved VCP inhibitors can significantly enhance radioiodine uptake.2 ABSTRACT Radioiodine treatment fails ≥25% of patients with thyroid cancer and has been proposed as a potential treatment for breast cancer. Cellular iodide uptake is governed by the sodium iodide symporter (NIS), which is frequently mislocalized in thyroid and breast tumours. However, the trafficking of NIS to the plasma membrane (PM) is ill-defined. Through mass spectrometry, co-immunoprecipitation, cell surface biotinylation and proximity ligation assays we identify two proteins which control NIS subcellular trafficking: ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP). HiLo microscopy revealed ARF4 enhanced NIS trafficking in co-incident PM vesicles, governed by a Cterminal VXPX motif, whilst papillary thyroid cancers (PTC) demonstrate repressed ARF4 expression.In contrast, VCP, the central protein in ER-associated degradation, specifically bound NIS and decreased its PM localization. Five chemically distinct allosteric VCP inhibitors all overcame VCPmediated repression of NIS function. In mice, two re-purposed FDA-approved VCP inhibitors significantly enhanced radioiodine uptake into thyrocytes, whilst human primary thyrocytes showed similar increases. Critically, PTC patients with high tumoural VCP expression who received radioiodine had strikingly worse disease-free survival. These studies now delineate the mechanisms of NIS trafficking, and for the first time open the therapeutic possibility of systemically enhancing radioiodine uptake in patients via FDA-approved drugs. 24), MAPK pathway/BRAF inhibitors (5,6, 25), multi-targeted kinase inhibitors (26) and HDAC inhibitors (27). Multiple biologically-targeted drugs have been evaluated in phase I, II and III trials, with several agents including sorafenib (6), lenvatinib (28) and dabrafenib (7) showing promising responses and/or disease stabilisation. However, issues of toxicity and drug resistance remain.To actively transport iodide for thyroid hormone biosynthesis and radioiodine treatment, NIS must be present in the basolateral PM of thyroid follicular cells. However, relatively little is known about the mechanisms that govern NIS trafficking. TSH induces iodide uptake through upregulation of NIS expression and modulation of its subcellular localisation (29-31).Yet, many thyroid cancers demonstrate reduced NIS activity through diminished PM retention (32-34). BRAF-mutant tumours (60-70% of thyroid cancers) are more likely to be resistant to radioiodine, partly due to decreased NIS expression (13,35), but also due to impaired PM targeting (11, 14), through mechanisms which remain ill-defined. Currently, PTTG1-binding factor (PBF) is the only protein shown to bind NIS and modulate its subcellular localisation (36).Early studies identified that breast tumours can uptake radioiodine (37,38), and subsequent studies confirmed functional NIS expression in up to...

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Emerging Cancer Therapeutic Targets in Protein Homeostasis

Bastola

Oien

Cooley

et al. 2018

AAPS J

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Genomic aberrations inside malignant cells through copy number alterations, aneuploidy, and mutations can exacerbate misfolded and unfolded protein burden resulting in increased proteotoxic stress. Increased proteotoxic stress can be deleterious to malignant cells; therefore, these cells rely heavily on the protein quality control mechanisms for survival and proliferation. Components of the protein quality control, such as the unfolded protein response, heat shock proteins, autophagy, and the ubiquitin proteasome system, orchestrate a cascade of downstream events that allow the mitigation of the proteotoxic stress. This dependency makes components of the protein quality control mechanisms attractive targets in cancer therapeutics. In this review, we explore the components of the protein homeostasis especially focusing on the emerging cancer therapeutic agents/targets that are being actively pursued actively.

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Heterozygous mutations in p97 and resistance to p97 inhibitors

Cited by 4 publications

References 7 publications

Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer

Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer

Pharmacologically targeting a novel pathway of sodium iodide symporter trafficking to enhance radioiodine uptake

Emerging Cancer Therapeutic Targets in Protein Homeostasis

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