Anti‐tumor activity of the HSP90 inhibitor SNX‐2112 in pediatric cancer cell lines

Chinn, Danielle C.; Holland, William; Yoon, Janet; Zwerdling, Theodore; Mack, Philip C.

doi:10.1002/pbc.23270

Cited by 16 publications

(14 citation statements)

References 31 publications

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“…Cells were then treated for 24 h prior to trypsinization and prepared for cell cycle analysis as previously described by Chinn et al (2011). Briefly, cells were re-suspended in 0.5 mL PBS (pH7.4) then fixed in a final concentration of 75 % ethanol and stored at −20 °C.…”

Section: Methodsmentioning

confidence: 99%

Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines

Holland

Chinn

Lara

et al. 2014

J Cancer Res Clin Oncol

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Purpose Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance. Methods The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance. Results The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested. Conclusions These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.

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Section: Methodsmentioning

confidence: 99%

Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines

Holland

Chinn

Lara

et al. 2014

J Cancer Res Clin Oncol

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“…To assess cell cycle effects following single-agent treatment with MK-5108, cells were seeded in 100-mm dishes (1.5 × 10 5 –5 × 10 5 cells) and treated at 0.4 μM for 6, 12, 24, 48, and 72 h, after which time they were harvested and stored at −20 °C until staining with propidium iodide (Roche, Indianapolis, IN) as described previously (Chinn et al 2012). Cell lines used to assess apoptosis via sub-G1 content for the MK-5108 + docetaxel combination were treated for 24 h at 0.5 μM MK-5108 and 1 nM docetaxel.…”

Section: Methodsmentioning

confidence: 99%

“…The representative cell lines, H1975, H460, H1335, and Calu-1 were plated at 2 × 10 6 –3.5 × 10 6 in 150-cm 2 dishes and treated for/harvested at the follow times: 6, 12, 24, 72 h. As previously described (Chinn et al 2012), SDS-PAGE was performed with 72 μg of protein per sample. Levels of phosphorylated Aurora A (p-Aur-A) (Th288) (C39D8, #3079), Aurora A/AIK (1G4, #4718), p-HH3 (Ser10) (D2C8, #3377), and histone H3 (D1H2, #4499) (Cell Signaling Technology, Danvers, MA) were determined.…”

Section: Methodsmentioning

confidence: 99%

Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies

Chinn

Holland

Mack

2014

J Cancer Res Clin Oncol

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Purpose Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. Methods Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. Results All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. Conclusions MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.

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“…Many clinical trials are focusing on treating OS using a variety of targeted therapies (1,25). Among them, HSP90 inhibition is a promising therapeutic strategy showing clinical activity in various tumor types, including OS (10,(26)(27)(28). Indeed, HSP90 client proteins are proteins playing crucial roles in establishing cancer cell hallmarks (29).…”

Section: Discussionmentioning

confidence: 99%

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Ory

Baud’huin

Verrecchia

et al. 2016

Clinical Cancer Research

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Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma.Experimental Design: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14 þ monocytes.

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Anti‐tumor activity of the HSP90 inhibitor SNX‐2112 in pediatric cancer cell lines

Cited by 16 publications

References 31 publications

Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines

Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines

Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

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