Evidence map›Paper›PMID 34607394›Full record

ArticleCancer research and treatment2022

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 and 5 more

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Article in Cancer research and treatment, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.3field-weighted citation impact, top 43% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 6 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 5 institutions in 2 countries.

Shinkyo YoonDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Hannah YangDivision of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Hyun-Min RyuDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eunjin LeeDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yujin JoDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Seyoung SeoDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Deokhoon KimDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Chang Hoon LeeBio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Wanlim KimDepartment of Orthopaedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kyung Hae JungDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sook Ryun ParkDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eun Kyung ChoiCenter for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sang-We KimDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kang-Seo ParkDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dae Ho LeeDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
University of Ulsan · KRUlsan College · KRAsan Medical Center · KRCHA University Bundang Medical Center · KRKorea Research Institute of Chemical Technology · KR

Funding

Korea Health Industry Development InstituteMinistry of Health and Welfare HI20C1586Ministry of Science and ICTNational Research Foundation of Korea 2018M3A9E2024004National Research Foundation of Korea 2020R1A2C1012506
6 · The paper itself

Abstract

purposeHeat 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

methodsWe established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.

resultsWe 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.

conclusionThe 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.

Indexed as

Antineoplastic AgentsCarcinoma, Non-Small-Cell LungLung NeoplasmsMicroRNAsCell Line, TumorDrug Resistance, NeoplasmFocal Adhesion Protein-Tyrosine KinasesHSP90 Heat-Shock ProteinsHumansIntegrin alphaVbeta3Proto-Oncogene Proteins p21(ras)Antineoplastic AgentsFocal Adhesion Protein-Tyrosine KinasesHSP90 Heat-Shock ProteinsIntegrin alphaVbeta3KRAS protein, humanMicroRNAsProto-Oncogene Proteins p21(ras)Combination therapyHSP90 inhibitorIntegrinKRAS mutationNSCLC

Identifiers

PMID34607394
PMCPMC9296920
OpenAlexW3202503252

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.