{
  "abstract": "Targeted protein degradation technologies-particularly proteolysis-targeting chimeras (PROTACs)-have recently emerged as powerful tools in cancer therapy. However, it remains unclear whether tumor cells can mount immediate responses to proteolysis, potentially leading to acquired resistance and diminished therapeutic efficacy. This critical knowledge gap prompted us to investigate the underlying mechanisms and to develop preventive strategies. Here, we synthesized a PROTAC molecule targeting anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC), termed ALK-PROTAC (AP). We confirmed the presence of immediate adaptive resistance responses following AP withdrawal, characterized by rapid re-expression of ALK and accelerated cellular proliferation. Mechanistically, these adaptive responses were driven by a cascade of metabolic remodeling events, including enhanced glucose and purine metabolism, along with upregulation of genes associated with reactive oxygen species (ROS) and hypoxia responses. These processes were closely linked to mitochondrial function, thereby increasing energy production in ALK+ NSCLC cells after AP withdrawal, upregulating mitochondrial anti-apoptotic proteins, and enhancing the transcriptional activity of Yes-associated protein 1 (YAP1). To overcome this resistance, we leveraged the metabolism-disrupting properties of bisphosphonates, specifically alendronate sodium (Aln), which induces mitochondrial dysfunction and metabolic perturbation via inhibition of the mevalonate pathway. We subsequently developed alendronate-calcium coordination nanoparticles encapsulating AP (Aln-AP NPs). As anticipated, Aln-AP NPs disrupted metabolic profiles, induced mitochondrial dysfunction, and abrogated AP-induced upregulation of anti-apoptotic proteins and YAP1. This intervention significantly delayed ALK re-expression and improved therapeutic outcomes both in vitro and in vivo. Collectively, these findings support metabolic intervention as an effective strategy to counteract immediate resistance to PROTAC-mediated proteolysis, addressing a key challenge in the field, expanding the scope of targeted protein degradation, and offering a novel approach to optimizing therapeutic efficacy.",
  "abstract_shown": true,
  "affiliations": [
    "Beijing Key Laboratory of Advanced Pharmaceutical Preparation, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.",
    "Department of Pharmacy, Capital Center for Children's Health, Capital Medical University, Beijing, 100020, China.",
    "Peking University Hospital of Stomatology, Beijing, 100081, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Jing Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Liuqing Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhicheng Yan"
    },
    {
      "affs": [
        0
      ],
      "name": "Qinghua Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaojia Jiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Meifang Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Hua Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenbing Dai"
    },
    {
      "affs": [
        0
      ],
      "name": "Xueqing Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Qiang Zhang"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Bing He"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ar0ffk6pqfthr.bib",
  "cited_by": 0,
  "doi": "10.1016/j.ajps.2026.101205",
  "fulltext_url": "https://europepmc.org/articles/PMC13744382",
  "id": "ar0ffk6pqfthr",
  "issns": [
    "1818-0876",
    "2221-285X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42999747",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7220672695",
  "pdf_url": "https://europepmc.org/articles/PMC13744382?pdf=render",
  "pmcid": "PMC13744382",
  "pmid": "42999747",
  "published": "2026-10-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ar0ffk6pqfthr.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42999747",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42999747"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Alendronate-mineralized nanoparticles loaded with ALK-PROTAC reverse the resistance and rebound effects of ALK⁺ NSCLC to PROTAC therapy by disrupting the mitochondria-linked feedback.",
  "title_text": "Alendronate-mineralized nanoparticles loaded with ALK-PROTAC reverse the resistance and rebound effects of ALK⁺ NSCLC to PROTAC therapy by disrupting the mitochondria-linked feedback.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/ar0ffk6pqfthr",
  "venue": "Asian journal of pharmaceutical sciences",
  "versions": []
}