A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells

We report the development, characterization, and validation of a peptide specific for the extracellular domain of HER2. This probe chemistry was developed for molecular imaging by using a structural model to select an optimal combination of amino acids that maximize the likelihood for unique hydrophobic and hydrophilic interactions with HER2 domain 3. The sequence KSPNPRF was identified and conjugated with either FITC or Cy5.5 via a GGGSK linker using Fmoc-mediated solid-phase synthesis to demonstrate fiexibility for this chemical structure to be labeled with different fluorophores. A scrambled sequence was developed for control by altering the conformationally rigid spacer and moving both hydrophobic and hydrophilic amino acids on the C-terminus. We validated peptide specificity for HER2 in knockdown and competition experiments using human colorectal cancer cells in vitro, and measured a binding affinity of kd = 21 nM and time constant of k = 0.14 min−1 (7.14 min). We used this peptide with either topical or intravenous administration in a preclinical model of colorectal cancer to demonstrate specific uptake in spontaneous adenomas and to show feasibility for real time in vivo imaging with near-infrared fluorescence. We used this peptide in immunofluorescence studies of human proximal colon specimens to evaluate specificity for sessile serrated and sporadic adenomas. Improved visualization can be used endoscopically to guide tissue biopsy and detect premalignant lesions that would otherwise be missed. Our peptide design for specificity to HER2 is promising for clinical translation in molecular imaging methods for early cancer detection.

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“…By comparison, antibodies can stimulate the HER2 pathway and potentially accelerate cell proliferation and tumorigenesis. 45-50 …”

Section: Discussionmentioning

confidence: 99%

Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2

et al. 2015

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“…In vivo study found that KU004 reduced growth of NCI-N87 xenograft dramatically in a dose-dependent manner by inducing apoptosis. These in vivo and in vitro results indicate that KU004 has the potential to treat HER2 + BC in the future (76).…”

Section: Her2 Tk Inhibitorsmentioning

confidence: 66%

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

et al. 2018

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Abstract.Human epidermal growth factor receptor-2 positive breast cancer (HER2 + BC) is characterized by a high rate of metastasis and drug resistance. The advent of targeted therapy drugs greatly improves the prognosis of HER2 + BC patients. However, drug resistance or severe side effects have limited the application of targeted therapy drugs. To achieve more effective treatment, considerable research has concentrated on strategies to overcome drug resistance. Abemaciclib (CDK4/6 inhibitor), a new antibody-drug conjugate (ADC), src homology 2 (SH2) containing tyrosine phosphatase-1 (SHP-1) and fatty acid synthase (FASN) have been demonstrated to improve drug resistance. In addition, using an effective vector to accurately deliver drugs to tumors has shown good application prospects. Many studies have also found that natural anti-cancer substances produced effective results during in vitro and in vivo anti-HER2 + BC research. This review aimed to summarize the current status of potential clinical drugs that may benefit HER2 + BC patients in the future.

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“…21 Cell cycle dysregulation is the hallmark of cancer. 22 Cell cycle arrest can lead to inhibition of cell growth. 23 Therefore, in our study, we further confirmed whether cell growth inhibition in gastric cancer cells was associated with cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

<p>Knockdown of ROS proto-oncogene 1 inhibits migration and invasion in gastric cancer cells by targeting the PI3K/Akt signaling pathway</p>

Jian¹,

Sun³

et al. 2019

OTT

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Objectives: Gastric cancer ranks the fourth most common cancer and the third leading cause of cancer mortality in the world. ROS proto-oncogene 1 (ROS1) is an oncogene and ROS1 rearrangement has been reported in many cancers. Our study aimed to investigate the potential function and the precise mechanisms of ROS1 in gastric cancer. Methods: In our study, the analysis of ROS1 expression and clinical pathologic factors of gastric cancer in gastric cancer using TCGA database demonstrated that ROS1 expression was elevated in gastric cancer and related to T, N, M and TNM staging. High expression of ROS1 predicted poor survival in patients with gastric cancer. Then, we measured ROS1 expression in four human gastric cancer cell lines and knocked down ROS1 expression in BGC-823 and SGC-7901 cells by specific shRNA transfection via Lipofectamine 2000. The effect of ROS1 knockdown on cell proliferation, cell cycle distribution, cell apoptosis and metastasis in vitro was evaluated by MTT, colony formation, flow cytometric analysis, wound healing and Transwell invasion assays. The levels of apoptosis-related proteins, EMT markers and the PI3K/Akt signaling pathway members were measured by Western blotting. Results: We demonstrated that shROS1 transfection markedly downregulated ROS1 expression in BGC-823 and SGC-7901 cells. Knockdown of ROS1 inhibited cell survival, clonogenic growth, migration, invasion and epithelial-mesenchymal transition (EMT), as well as induced cell cycle arrest and apoptosis in gastric cancer cells. Furthermore, ROS1 knockdown inhibited the phosphorylation of PI3K and Akt. Conclusion: Collectively, our data suggest that ROS1 may serve as a promising therapeutic target in gastric cancer treatment.

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A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells

Cited by 9 publications

References 38 publications

Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2

Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

<p>Knockdown of ROS proto-oncogene 1 inhibits migration and invasion in gastric cancer cells by targeting the PI3K/Akt signaling pathway</p>

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