Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China.
Adv Sci (Weinh). 2024 Sep;11(34):e2401171. doi: 10.1002/advs.202401171. Epub 2024 Jul 8.
Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST.
瑞普替尼是一种广泛抑制 KIT 和 PDGFRA 受体酪氨酸激酶的药物，被指定为胃肠道间质瘤（GIST）的四线治疗药物。它适用于对伊马替尼、舒尼替尼和regorafenib耐药的患者。随着其应用的增加，对瑞普替尼耐药的情况越来越常见。不幸的是，目前对于对瑞普替尼耐药的患者，尚无科学成熟的治疗选择。翻译后修饰（PTMs）如泛素化，与其与其他修饰的相互作用一起，在调节肿瘤发生和进展中发挥集体作用。然而，泛素化与瑞普替尼耐药之间的具体关联尚未报道。通过蛋白质组-泛素组测序，在瑞普替尼耐药的 GIST 中检测到 USP5 蛋白水平升高和泛素化减少。随后对质谱结果的检查通过泛素化验证了 TRIM21 通过泛素化调控 USP5 表达的相互作用，而 USP5 通过去泛素化调控 MDH2 表达，从而促进 GIST 中的瑞普替尼耐药。此外，ZDHHC18 可以棕榈酰化 MDH2，防止其泛素化并进一步增加其蛋白质稳定性。该研究强调了翻译后修饰（特别是泛素化）与耐药性之间的相关性，强调了靶向 USP5-MDH2 轴以对抗 GIST 中瑞普替尼耐药的潜力。
