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논문 기본 정보

자료유형
학술저널
저자정보
윤신교 (서울아산병원) 양한나 (분당차병원) 류현민 (서울아산병원) 이은진 (서울아산병원) 조유진 (서울아산병원) 서세영 (서울아산병원) 김덕훈 (서울아산병원) 이창훈 (한국화학연구원) 김완림 (서울아산병원) 정경해 (울산대학교) 박숙련 (울산대학교) 최은경 (서울아산병원) 김상위 (울산대학교) 박강서 (울산대학교) 이대호 (울산대학교)
저널정보
대한암학회 Cancer Research and Treatment Cancer Research and Treatment 제54권 제3호
발행연도
2022.7
수록면
767 - 781 (15page)
DOI
10.4143/crt.2021.651

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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 <i>in vitro</i> and <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i>, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

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