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- Lung and Thoracic cancer
- Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer
- Shinkyo Yoon, Hannah Yang, Hyun-Min Ryu, Eunjin Lee, Yujin Jo, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Wanlim Kim, Kyung Hae Jung, Sook Ryun Park, Eun Kyung Choi, Sang-We Kim, Kang-Seo Park, Dae Ho Lee
- Cancer Res Treat. 2022;54(3):767-781. Published online September 30, 2021
- DOI: https://doi.org/10.4143/crt.2021.651
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Abstract
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Supplementary Material
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ePub - Purpose
Heat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.
Materials and Methods
We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.
Results
We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.
Conclusion
The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC. -
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- Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis
Dihua Huang, Feng Xu, Luohang Xu, Zekai Tang, Yanxin Hu, Jiandong Li, Jianhua Yu
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2025; 1871(5): 167814. CrossRef - Integrins in Cancer Drug Resistance: Molecular Mechanisms and Clinical Implications
Yoshinobu Kariya, Michiru Nishita
International Journal of Molecular Sciences.2025; 26(7): 3143. CrossRef - Integrin αV Inhibition by GMI, a Ganoderma Microsporum Immunomodulatory Protein, Abolish Stemness and Migration in EGFR‐Mutated Lung Cancer Cells Resistant to Osimertinib
Yu‐Ting Kang, Hui‐Yi Chang, Ya‐Chu Hsieh, Chia‐Hsuan Chou, I‐Lun Hsin, Jiunn‐Liang Ko
Environmental Toxicology.2024; 39(12): 5238. CrossRef - Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway
Kaitao Zhu, Shiwei Li, Hongru Yao, Jilong Hei, WenGuo Jiang, Tracey Martin, Shanyi Zhang
Journal of Neuro-Oncology.2024; 170(2): 331. CrossRef - Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence
Bashar Alhasan, Marina Mikeladze, Irina Guzhova, Boris Margulis
Cancer and Metastasis Reviews.2023; 42(1): 217. CrossRef
- Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis
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- Effects of Integrin avB5 and av B53 on the Adenovirus - Mediated Gene Transduction
- J Y Park, S Y Joo, H S Jeon, H J Chang, S Kam, I S Kim
- J Korean Cancer Assoc. 2000;32(2):422-430.
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Abstract
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- PURPOSE
Human adenovirus, commonly used as a vector for gene therapy, enters host cells by receptor mediated endocytosis. Since integrin av B5 of cell surface promotes endocytosis of adenovirus and subsequent disruption of endosome, we hypothesized that the level of integrin av B5 of target cells may determine the efficiency of adenovirus- mediated gene transfer and its therapeutic effects.
MATERIALS AND METHODS
We transduced lacZ gene or herpes simplex virus thymidine kinase (HSVtk) gene, using adenoviral vector, into human lung cancer cell lines (H1299, H157, and H322). Then we evaluated the relationship between the level of integrin av B5 and av 53 of target cells, and adenovirus-mediated gene transduction efficiency.
RESULTS
The trasduction efficiency, observed by X-gal stain and B-gal activity after infection of recombinant-adenovirus encoding lacZ gene, was correlated with the level of integrin av B5, assessed by Western blotting. The bystander mediated cell killing, after transduction of HSVtk gene, was also correlated with the level of integrin av B5 of cell lines.
CONCLUSION
These results suggest that quantitative measurement of the level of integrin av B5 of target cells may be a useful predictor of the efficiency and effectiveness of gene transfer by means of an adenoviral vector.
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