YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer.

IF 10 1区 医学 Q1 ONCOLOGY
Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Hayato Kawachi, Masaki Ishida, Yohei Matsui, Soichi Hirai, Ryota Nakamura, Kenji Morimoto, Naoki Furuya, Sachiko Arai, Yasuhiro Goto, Yoshihiko Sakata, Kazumi Nishino, Michiko Tsuchiya, Akihiro Tamiya, Go Saito, Satoshi Muto, Takayuki Takeda, Koji Date, Yasuhito Fujisaka, Satoshi Watanabe, Daichi Fujimoto, Hisanori Uehara, Mano Horinaka, Toshiyuki Sakai, Seiji Yano, Shinsaku Tokuda, Koichi Takayama
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引用次数: 0

Abstract

Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.

Experimental design: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment YAP expression and correlated with treatment outcomes.

Results: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.

Conclusion: The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

YAP调节RET异常癌症中HER3信号驱动的对RET抑制剂的适应性抗性。
目的:转染过程中的重排(RET)畸变是几种肿瘤类型中的靶向癌基因,RET抑制剂具有显著疗效。然而,一些RET畸变癌症患者对RET酪氨酸激酶抑制剂(TKIs)不敏感。最近,耐药机制作为克服耐药性的初始疗法靶点引起了人们的关注。用来自RET异常癌细胞的RET-TKIs治疗耐药细胞出现的基本机制仍不清楚。本研究探讨了YAP介导的HER3信号在RET-异常癌细胞对RET-TKIs产生适应性耐药性的内在机制中的作用:实验设计:使用四种RET异常癌细胞系评估对RET-TKIs selpercatinib和pralsetinib的敏感性,并使用RNA测序、磷酸化RTK抗体阵列、染色质免疫共沉淀分析和荧光素酶报告实验阐明适应性耐药的分子机制。对RET融合阳性肺癌患者的临床标本进行了治疗前YAP表达分析,并将其与治疗结果相关联:结果:在高YAP表达的RET异常癌细胞中,YAP介导的HER3信号激活可维持细胞存活,并诱导出现对RET-TKIs selpercatinib和pralsetinib耐受的细胞。泛ErBB抑制剂阿法替尼和YAP/TEAD抑制剂verteporfin和K-975可使YAP表达的RET异常癌细胞对RET-TKIs selpercatinib和pralsetinib敏感。在RET融合阳性肺癌患者的临床标本中,治疗前YAP的表达与RET-TKI治疗效果不佳有关:结论:YAP-HER3轴对于接受RET-TKIs治疗的高YAP表达RET异常癌细胞的生存和适应性耐药至关重要。将YAP/HER3抑制与RET-TKIs相结合是一种高效的初始治疗策略。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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