JOURNAL OF EXPERIMENTAL MEDICINE
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2025
·Vol. 222
·期 3
·e20241147
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IF 10.6
He Ying,Li Wei,Zhang Meiling,Wang Hui,Lin Peilu,Yu Ying,Huang Bin,Hao Meng,He Jianuo,Kong Weiyao,Luo Dan,Xu Tengteng,Wang Jiaqi,Huang Ying,Zhao Qinwen,Liu Ying,Zhang Jie,Nian Yong,Zhang Lei,Zhu Bo,Yin Chengqian
BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non–receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
·
IF 8
Ayimukedisi Yalikong,Xu-Quan Li,Ping-Hong Zhou,Zhi-Peng Qi,Bing Li,Shi-Lun Cai,Yun-Shi Zhong
Background Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents.Methods HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured.Results TPLNP was small in nanosize (73.4±5.2nm) with narrow size distribution (PDI=0.15±0.02) and favorable zeta potential (pH=9.6, zeta potential: −57.3±6.69mV; pH=7.0, zeta potential: −28.7±5.1mV; pH=5.6, zeta potential: −21.1±4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo.Conclusion TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Lili Zou,Weiping Ding,Yuanyuan Zhang,Shaohui Cheng,Fenfen Li,Renquan Ruan,Pengfei Wei,Bensheng Qiu
Vemurafenib is a chemotherapeutic drug recently approved by the FDA to treat melanoma. Because the drug is usually delivered orally, the route of administration readily causes damage to major organs with limited antitumor efficacy and bioavailability. In this study, we developed a peptide-modified vemurafenib-loaded liposome for the targeted inhibition of subcutaneous melanoma via the skin. First, the peptide-modified vemurafenib-loaded liposomes (Vem-TD-Lip) were prepared and characterized with respect to the size, shape and charge; the loading efficiency of vemurafenib; and the stability. Then, the intracellular uptake of these liposomes, their limited cytotoxicity, the selective inhibition of melanoma cells harboring BRAF mutations, and the liposome permeation ability were confirmed through in vitro experiments. Finally, the safety and antitumor activity of Vem-TD-Lip were evaluated in vivo . The results showed that transdermal delivery of Vem-TD-Lip effectively targeted and inhibited subcutaneous melanoma in male mice, the administration of Vem-TD-Lip through skin was better than that through oral administration and intravenous injection in terms of reducing damage to major organs and enhancing antitumor efficacy, and the peptide TD significantly enhanced the delivery of Vem-TD-Lip across the skin. This work provides a new strategy for delivering vemurafenib to target and inhibit subcutaneous melanoma.
研究领域:
药学
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肿瘤学
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
BIOELECTROCHEMISTRY
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2025
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IF 4.5
Ai Ting Cai,Qing Ping Fu,Ming Zhong Sun,Hong Mei Chen,Yun Gang Wang,Hui Xiang Jv
The detection of BRAF mutations in circulating tumor DNA is beneficial for early diagnosis and personalized therapeutic approaches of melanoma. However, the sensitive and reliable trace detection of BRAF mutations remains a major challenge. Therefore, in this study, the combination of two isothermal signal amplification techniques (primer exchange reaction (PER) and hybridization chain reaction (HCR)) was proposed to construct an electrochemical biosensor for the efficient and sensitive detection of BRAF mutations. The presence of target triggered PER and HCR sequentially to achieve dual-cascade amplification of positive electrochemical signal feedback. Compared to the detection limit (1.27 pM or 0.23 pM) of single-signal amplification technology (PER or HCR), the detection limit of dual-signal amplification techniques was significantly lower (0.34 fM). In addition, the dual-signal amplification strategy exhibited other excellent sensing properties, such as a wide linear detection range (0.01 pM to 1 nM), excellent specificity, satisfactory reproducibility and stability, and the ability to achieve low-level target detection in diluted serum samples. Based on all of these features, the proposed strategy indicate broad application prospects for detecting low-abundance nucleic acid targets in clinical samples.
研究领域:
生物传感器
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分子诊断
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生物化学
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癌症研究
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分析化学
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遗传学
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电化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
·
IF 6.8
Wen Shuai,Huan Xiao,Panpan Yang,Yiwen Zhang,Faqian Bu,Yongya Wu,Qiu Sun,Guan Wang,Liang Ouyang
The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.
研究领域:
肿瘤学
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药理学
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药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）