DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp90-Cdc37 interaction

Chen, Xiangling; Liu, Peng; Wang, Quanren; Li, Yun; Li, Fu; Fu, Haoyu; Zhu, Jianming; Chen, Zhaoqiang; Zhu, Weiliang; Xie, Conghua; Lou, Liguang

doi:10.1016/j.canlet.2018.07.012

Cited by 35 publications

(32 citation statements)

References 36 publications

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“…In the current study, we found that SHR6390 exhibited even greater potency against the trastuzumab‐resistant BT‐474/T cell line than against parental BT‐474 cells. Our previous study showed that enhanced expression of epidermal growth factor receptor (EGFR), as well as elevated levels of p‐AKT and p‐ERK may be responsible for the resistance to trastuzumab in BT‐474/T cells . These results are compatible with those of a previous study suggesting that CDK4/6 blockade reduced TSC2 phosphorylation, leading to attenuation of mTORC1 activity, an effect that was shown to relieve feedback inhibition of EGFR family kinases and thus sensitized the respective cells to EGFR/HER2 blockade.…”

Section: Discussionsupporting

confidence: 84%

“…Strikingly, SHR6390 demonstrated similar potency in MCF7/TR cells and parental MCF7 cells, with an IC 50 value of 229.5 and 115.4 nmol/L, respectively (Figure C). Furthermore, the BT‐474/T cell line, which has been demonstrated to possess resistance to the HER2‐targeted antibody trastuzumab, was even more sensitive to SHR6390 than the parental BT‐474 cell line, exhibiting IC 50 values of 626.8 and 210.7 nmol/L in parental and BT‐474/T resistant cell lines, respectively (Figure D).…”

Section: Resultsmentioning

confidence: 99%

“…The tamoxifen‐resistant cell line MCF7/TR was established by culturing MCF7 cells with gradually increasing concentrations of tamoxifen. The trastuzumab‐resistant cell line BT‐474/T was established from the BT474 cell line as described previously …”

Section: Methodsmentioning

confidence: 99%

“…The trastuzumab-resistant cell line BT-474/T was established from the BT474 cell line as described previously. 18…”

Section: Cell Lines and Culturementioning

confidence: 99%

“…Strikingly, SHR6390 demonstrated similar potency in MCF7/TR cells and parental MCF7 cells, with an IC 50 value of 229.5 and 115.4 nmol/L, respectively ( Figure 1C). Furthermore, the BT-474/T cell line, which has been demonstrated to possess resistance to the HER2-targeted antibody trastuzumab, 18 was even more sensitive to SHR6390 than the paren- Irreversible cell cycle arrest can result in cellular senescence. 23 Next, senescence β-galactosidase staining was used to investigate whether SHR6390 could induce senescence.…”

Section: Shr6390 Inhibits the Proliferation Of Retinoblastoma-positmentioning

confidence: 99%

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Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Long

et al. 2019

Cancer Science

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Inhibition of the cyclin‐dependent kinase (CDK) 4/6‐retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB‐positive tumor cells in vitro, and exclusively induced G 1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780‐phosphorylated RB protein. Compared with the well‐known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2‐targeting antibody in ER‐positive and HER2‐positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER‐positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The trastuzumab-resistant cell line BT-474/T was established from the BT474 cell line as described previously. 18…”

Section: Cell Lines and Culturementioning

confidence: 99%

Section: Shr6390 Inhibits the Proliferation Of Retinoblastoma-positmentioning

confidence: 99%

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Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Long

et al. 2019

Cancer Science

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Mapping oncogenic protein interactions for precision medicine

Tabar

Francis

Yeo

et al. 2022

Intl Journal of Cancer

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Normal protein-protein interactions (normPPIs) occur with high fidelity to regulate almost every physiological process. In cancer, this highly organised and precisely regulated network is disrupted, hijacked or reprogrammed resulting in oncogenic protein-protein interactions (oncoPPIs). OncoPPIs, which can result from genomic alterations, are a hallmark of many types of cancers. Recent technological advances in the field of mass spectrometry (MS)-based interactomics, structural biology and drug discovery have prompted scientists to identify and characterise oncoPPIs. Disruption of oncoPPI interfaces has become a major focus of drug discovery programs and has resulted in the use of PPI-specific drugs clinically. However, due to several technical hurdles, studies to build a reference oncoPPI map for various cancer types have not been undertaken. Therefore, there is an urgent need for experimental workflows to overcome the existing challenges in studying oncoPPIs in various cancers and to build comprehensive reference maps. Here, we discuss the important hurdles for characterising oncoPPIs and propose a three-phase multidisciplinary workflow to identify and characterise oncoPPIs. Systematic identification of cancertype-specific oncogenic interactions will spur new opportunities for PPI-focused drug discovery projects and precision medicine.

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Linoleic‐acid‐substituted polyethylenimine to silence heat shock protein 90B1 (HSP90B1) to inhibit migration of breast cancer cells

Sundaram

Uludağ

2022

The Journal of Gene Medicine

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Introduction Breast cancer continues to be one of the leading causes of death in women, and the lack of treatment options for distant metastasis warrants the need to identify and develop more effective approaches. The aim of this study was to identify and validate targets that are associated with the survival and migration of the breast cancer cells in vitro through RNA interference (RNAi) approach. Methods Linoleic‐acid‐modified polyethylenimine (PEI) polymer was used to screen a short interfering RNA (siRNA) library against numerous cell adhesion and cytoskeleton genes in MDA‐MB‐231 triple‐negative breast cell line, and the functional outcome of silencing was determined by growth and migration inhibition with further target validation studies. Results Heat shock protein 90B1 (HSP90B1) was identified as a crucial gene that is known to be involved in various breast cancer machineries, including uncontrolled proliferation and brain metastasis. The success of this approach was also due to the use of hyaluronic acid (HA) additive in lipopolymer complexes that showed a profound impact in reducing the cell viability (~50%), migration (~40%), and mRNA transcript levels (~80%) with a physiologically relevant siRNA concentration of 60 nM. The use of Dicer‐substrate siRNA proved to be beneficial in target silencing, and a combinational treatment of integrin‐β1 (ITGB1) and HSP90B1 was effective in reducing the migration of the MDA‐MB‐231 and MDA‐MB‐436 breast cancer cells. Conclusion This study demonstrates the potential to identify and silence targets using a lipid‐modified PEI/siRNA system and highlights the importance of HSP90B1 in the growth and migration of breast cancer cells.

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DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp90-Cdc37 interaction

Cited by 35 publications

References 36 publications

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Mapping oncogenic protein interactions for precision medicine

Linoleic‐acid‐substituted polyethylenimine to silence heat shock protein 90B1 (HSP90B1) to inhibit migration of breast cancer cells

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