MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways

Saiki, Anne Y.; Caenepeel, Sean; Yu, Dongyin; Lofgren, Julie A.; Osgood, Tao; Robertson, Rebecca; Canon, Jude; Su, Cheng; Jones, Adrie; Zhao, Xiaoning; Deshpande, Chetan; Payton, Marc; Ledell, Jebediah; Hughes, Paul E.; Oliner, Jonathan D.

doi:10.18632/oncotarget.1918

Cited by 46 publications

(49 citation statements)

References 47 publications

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“…This intriguing pattern implies that restoring p53 function and blocking the MAPK pathway at the same time could be more beneficial to SKCM patients than interfering with either pathway alone. Studies have shown increased apoptosis and inhibition of melanoma growth by combining a BRAF inhibitor and p53 reactivation (Lu et al, 2013; Saiki et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Leighton

Wang

et al. 2018

Cell Reports

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SUMMARY Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Leighton

Wang

et al. 2018

Cell Reports

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“…To measure combination effects in excess of Loewe additivity, Horizon has devised a scalar measure to characterize the strength of synergistic interaction termed the Synergy Score [13,14]. The Synergy Score equation integrates the experimentally-observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe model for additivity.…”

Section: Analysis Of Combination Screening Resultsmentioning

confidence: 99%

“…Detailed methods on the combination assay were reported in [14]. Combinations were analyzed using Synergy Score and Loewe Volume Score, as described in [15,16] using Horizon's proprietary Chalice TM Analyzer software.…”

Section: Methodsmentioning

confidence: 99%

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Toshimitsu¹

2015

Glob J Cancer Ther

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Eribulin sensitivity was examined in a panel of twenty-five human cancer cell lines representing a variety of tumor types, with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as a topoisomerase I inhibitor (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin.of care. Chemotherapeutic drugs are often most effective when given in combination, in particular when synergistic killing is achieved without additive toxicity. To date, potential combination therapies for eribulin have been explored with only a limited number of anticancer agents. We therefore have performed an in vitro study of eribulin combined with 34 anticancer agents in 25 different tumor cell lines of various types, through use of a combination high throughput screening (cHTS) platform. Our goals were to identify drugs that might be paired with eribulin to increase clinical efficacy in metastatic breast cancer, to identify drugs that convert eribulin non-responders to responders, and to identify new therapeutic indications for eribulin utilization. Several compelling synergy effects with approved and emerging drugs were observed. The preclinical data provides insights about future clinical development strategies.

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“…IC 50 values were calculated using a 4-parameter logistic model in GeneData Screener (Genedata AG). Growth inhibition (GI) was calculated on a 200% scale as described previously (23).…”

Section: Tumor Cell Line Viability Screeningmentioning

confidence: 99%

In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models

Hughes

Rex

Caenepeel

et al. 2016

Molecular Cancer Therapeutics

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The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were MET-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying MET copy numbers revealed that high-level focal MET amplification (>12 copies) was required to confer MET oncogene addiction and AMG 337 sensitivity. One MET-amplified cell line, H1573 (>12 copies), was AMG 337 insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive MET-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; >90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors.

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MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways

Cited by 46 publications

References 47 publications

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models

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