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

Oncogene volume 44, pages 3461–3475 (2025)Cite this article

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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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Fig. 1: ACK1i impairs mitochondria and invokes mitophagy in NSCLC cells.
Fig. 2: ACK1 inhibitors elicit mitophagy via the BNIP3/PINK1/PARKIN pathway in NSCLC cells.
Fig. 3: ACK1 and RFX2 interacted in NSCLC cells with the MHR domain of ACK1 responsible for binding to RFX2.
Fig. 4: ACK1i promotes MIB1-mediated ubiquitination and proteasomal degradation of RFX2 in NSCLC cells.
Fig. 5: RFX2 directly binds the BNIP3 promoter and transcriptionally suppresses BNIP3 expression in NSCLC cells.
Fig. 6: ACK1i induces adaptive mitophagy through the downregulation of the RFX2-BNIP3 axis.
Fig. 7: Mitophagy inhibitors increase the response of NSCLC to ACK1 inhibition.
Fig. 8: Mdivi-1 overcomes NSCLC’s tolerance to anti-ACK1 therapy in vivo.

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Data availability

Public data used in this work can be acquired from (TCGA, https://www.cancer.gov/tcga/). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.

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Acknowledgements

This work was supported by the Natural Science Foundation of China [82172786], Heilongjiang Provincial Natural Science Foundation of China [ZD2024H003], Beijing Xisike Clinical Oncology Foundation (Y-2024AZ(EGFR) MS-0187), the Climbing Program of Harbin Medical University Cancer Hospital [PDYS2024-02] and the National Cancer Center Climbing Fund of China [NCC201908B06].

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  1. These authors contributed equally: Kui Cao, Shenshui Wei, Tianjiao Ma, Xiaolong Zou.

Authors and Affiliations

  1. Department of Thoracic Surgery, Harbin Medical University Cancer hospital, Harbin, Heilongjiang, China

    Kui Cao, Mengdi Lu & Jianqun Ma

  2. Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China

    Shenshui Wei, Yuning Wang, Xiangrong He & Jinhong Zhu

  3. Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Tianjiao Ma

  4. Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Xiaolong Zou

  5. Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China

    Hongxue Meng & Xinxin Yang

  6. Biobank, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, China

    Jinhong Zhu

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Contributions

All authors contributed to the study’s conception and design. Data preparation, collection, and analysis were performed by Kui Cao, Shenshui Wei, Tianjiao Ma, Jinhong Zhu, Jianqun Ma, Hongxue Meng, Xinxin Yang, Mengdi Lu, Yuning Wang, Xiangrong He. Jinhong Zhu and Mengdi Lu accessed and verified the underlying data. Reconciliation of underlying data was solved by Jianqun Ma and Jinhong Zhu. The draft of the manuscript was written by Jinhong Zhu, Kui Cao, and Jianqun Ma. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Cao, K., Wei, S., Ma, T. et al. RFX2-BNIP3 axis-driven adaptive mitophagy promotes resistance to ACK1-targeted therapy in non-small cell lung cancer. Oncogene 44, 3461–3475 (2025). https://doi.org/10.1038/s41388-025-03502-0

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