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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. -
Citations
Citations to this article as recorded by
- Adaptive Feedback Signaling Through the FAK/SRC Pathway Promotes KRAS G12C Inhibitor Resistance
Hibiki Udagawa, Yuji Shibata, Monique B. Nilsson, Kazuya Nishii, Jacqulyne P. Robichaux, Ana Galan-Cobo, Junqin He, Alissa Poteete, Yu Qian, David Molkentine, Xiaoxing Yu, Qian Huang, Marcelo V. Negrao, John V. Heymach
Journal of Thoracic Oncology.2026; : 103991. CrossRef - 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
- Adaptive Feedback Signaling Through the FAK/SRC Pathway Promotes KRAS G12C Inhibitor Resistance
- 12,464 View
- 296 Download
- 5 Web of Science
- 6 Crossref
- Sarcoma
- Clinicopathologic Characteristics and Clinical Outcome of Localized Liposarcoma: A Single-Center Experience over 25 Years and Evaluation of PD-L1 Expression
- Heejung Chae, Jeong Eun Kim, Wanlim Kim, Jong-Seok Lee, Si Yeol Song, Min Hee Lee, Hye Won Chung, Kyung-Ja Cho, Joon Seon Song, Jin-Hee Ahn
- Cancer Res Treat. 2022;54(2):579-589. Published online July 6, 2021
- DOI: https://doi.org/10.4143/crt.2021.496
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Abstract
PDFSupplementary MaterialPubReaderePub
- Purpose
For liposarcoma (LPS), clinical course and proper treatment strategies have not been well-established. Recently, immune-checkpoint inhibitors have shown potential efficacy in LPS. We aimed to describe the clinical course of LPS and evaluate the clinical impact of programmed death-ligand 1 (PD-L1).
Materials and Methods
We reviewed all consecutive patients (n=332) who underwent curative-intent surgery for localized LPS at Asan Medical Center between 1989 and 2017. PD-L1 testing was performed in well-differentiated and dedifferentiated LPS.
Results
The median age was 56 years with males comprising 60.8%. Abdomen-pelvis (47.6%) and well-differentiated (37.7%) were the most frequent primary site and histologic subtype, respectively. During a median follow-up of 81.2 months, recurrence was observed in 135 (40.7%), and 86.7% (117/135) were loco-regional. Well-differentiated subtype (hazard ratio [HR], 0.38), abdomen-pelvis origin (HR, 2.43), tumor size larger than 5 cm (HR, 1.83), positive resection margin (HR, 2.58), and postoperative radiotherapy (HR, 0.36) were significantly related with recurrence-free survival as well as visceral involvement (HR, 1.84) and multifocality (HR, 3.79) in abdomen-pelvis LPS. PD-L1 was positive in 31.5% (23/73) and 51.3% (39/76) of well-differentiated and dedifferentiated LPS, respectively, but had no impact on survival outcomes.
Conclusion
Clinical course of LPS was heterogeneous according to histology and anatomic location. Clear resection margin was important to lower recurrence and postoperative radiotherapy might have additional benefit. A decent portion of well-differentiated and dedifferentiated LPS were positive for PD-L1, but its prognostic role was unclear. Further research is needed to determine clinical implications of PD-L1, especially for advanced-stage LPS with unmet needs for effective systemic treatment. -
Citations
Citations to this article as recorded by- Recurrent Intrathoracic Liposarcoma: A Case Report and a Comprehensive Literature Review of a Rare Clinical Entity
Vasileios Leivaditis , Manfred Dahm , Athanasios Papatriantafyllou, Hans-Georg Keul, Lydia Kohl, Hans-Joachim Schäfers
Cureus.2024;[Epub] CrossRef - Clinicopathological Features of Intrathoracic Liposarcoma—A Systematic Review with an Illustrative Case
Kajetan Kiełbowski, Nikola Ruszel, Seweryn Adam Skrzyniarz, Małgorzata Edyta Wojtyś, Rafał Becht, Konrad Ptaszyński, Darko Gajić, Janusz Wójcik
Journal of Clinical Medicine.2022; 11(24): 7353. CrossRef
- Recurrent Intrathoracic Liposarcoma: A Case Report and a Comprehensive Literature Review of a Rare Clinical Entity
- 8,920 View
- 124 Download
- 1 Web of Science
- 2 Crossref
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