RFX2-BNIP3 axis-driven adaptive mitophagy promotes resistance to ACK1-targeted therapy in non-small cell lung cancer

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-07-25 DOI:10.1038/s41388-025-03502-0

Kui Cao, Shenshui Wei, Tianjiao Ma, Xiaolong Zou, Hongxue Meng, Xinxin Yang, Mengdi Lu, Yuning Wang, Xiangrong He, Jianqun Ma, Jinhong Zhu

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Abstract

Activated Cdc42-associated kinase 1 (ACK1) is an oncogenic non-receptor kinase that promotes tumor cell survival and impairs T-cell activation. Targeting ACK1 has great promise in cancer control. However, tumor adaptive responses that may limit the anticancer efficacy of ACK1 inhibition (ACK1i) remain unclear. We found that ACK1i treatment triggered the PINK1/PARKIN-mediated adaptive mitophagy by upregulating the mitophagy receptor BNIP3. Mass/Spectrometry and co-immunoprecipitation (Co-IP) results indicated that ACK1 interacted with transcription factor regulatory factor X 2 (RFX2) through its MHR domain, and competitively inhibits RFX2 ubiquitination via the E3 ubiquitin ligase MIB1. Conversely, ACK1i facilitates MIB1-mediated RFX2 ubiquitination and degradation. Moreover, we observed that RFX2 is a transcriptional suppressor of BNIP3 using luciferase reporter gene assays and chromatin immunoprecipitation (ChIP). Overall, ACK1i treatment causes RFX2 instability and thereby diminishes RFX2’s suppressive effects on BNIP3 transcription, leading to BNIP3 accumulation and the activation of mitophagy pathways. This adaptive mitophagy allows NSCLC cells to survive under ACK1 inhibition, potentially reducing the efficacy of ACK1i. ACK1i combined with mitophagy-inhibiting agents may attain a more accomplished response in NSCLC. In conclusion, ACK1i induced mitophagy through the release of RFX2 inhibition on BNIP3 transcription, thereby driving adaptive resistance. Inhibiting mitophagy sensitizes NSCLC to ACK1i.

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RFX2-BNIP3轴驱动的适应性自噬促进非小细胞肺癌对ack1靶向治疗的抗性。

活化的cdc42相关激酶1 （ACK1）是一种致癌的非受体激酶，可促进肿瘤细胞存活并损害t细胞活化。靶向ACK1在癌症控制中具有很大的前景。然而，可能限制ACK1抑制（ACK1i）抗癌功效的肿瘤适应性反应尚不清楚。我们发现ACK1i处理通过上调线粒体自噬受体BNIP3触发PINK1/ parkin介导的适应性线粒体自噬。质谱和共免疫沉淀（Co-IP）结果表明，ACK1通过其MHR结构域与转录因子调节因子x2 （RFX2）相互作用，并通过E3泛素连接酶MIB1竞争性地抑制RFX2的泛素化。相反，ACK1i促进mib1介导的RFX2泛素化和降解。此外，我们通过荧光素酶报告基因检测和染色质免疫沉淀（ChIP）观察到RFX2是BNIP3的转录抑制因子。总体而言，ACK1i处理导致RFX2不稳定，从而降低RFX2对BNIP3转录的抑制作用，导致BNIP3积累和线粒体自噬途径的激活。这种适应性有丝分裂允许NSCLC细胞在ACK1抑制下存活，可能降低ACK1i的功效。ACK1i联合有丝分裂抑制剂可能在非小细胞肺癌中获得更好的疗效。综上所述，ACK1i通过释放RFX2抑制BNIP3转录诱导有丝分裂，从而驱动适应性抗性。抑制线粒体自噬使NSCLC对ACK1i敏感。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.