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.

中文翻译：

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YAP 调节 RET 异常癌症中 HER3 信号传导驱动的对 RET 抑制剂的适应性耐药


目的：转染过程中重排 （RET） 畸变代表多种肿瘤类型的可靶向癌基因，RET 抑制剂显示出显著的疗效。然而，一些 RET 异常癌症患者对 RET 酪氨酸激酶抑制剂 （TKI） 不敏感。最近，耐药机制作为克服耐药性的初始治疗靶点引起了人们的关注。用源自 RET 异常癌细胞的 RET-TKI 处理的耐药细胞出现的潜在机制仍然未知。本研究调查了 YAP 介导的 HER3 信号在 RET 异常癌细胞对 RET-TKIs 适应性耐药的潜在机制中的作用。实验设计：使用四种 RET 异常癌细胞系评估对 RET-TKI selpercatinib 和 pralsetinib 的敏感性，并使用 RNA 测序、磷酸化 RTK 抗体阵列、染色质免疫沉淀测定和荧光素酶报告基因测定阐明适应性耐药的分子机制。分析 RET 融合阳性肺癌患者的临床标本治疗前 YAP 表达并与治疗结果相关。结果： 在高表达 YAP 的 RET 异常癌细胞中，YAP 介导的 HER3 信号激活维持细胞存活并诱导对 RET-TKIs selpercatinib 和 pralsetinib 耐受的细胞的出现。泛 ErBB 抑制剂阿法替尼和 YAP/TEAD 抑制剂维替泊芬和 K-975 使表达 YAP 的 RET 异常癌细胞对 RET-TKI selpercatinib 和 pralsetinib 敏感。从 RET 融合阳性肺癌患者获得的临床标本中治疗前 YAP 表达与 RET-TKI 治疗结局不良相关。 结论： YAP-HER3 轴对于接受 RET-TKIs 处理的高表达 YAP 异常癌细胞的存活和适应性抵抗至关重要。将 YAP/HER3 抑制与 RET-TKIs 相结合是一种高效的初始治疗策略。