Decoding sunitinib resistance in ccRCC: Metabolic-reprogramming-induced ABAT and GABAergic system shifts
Qian Zhang,
Lei Ding,
Ye Yan,
Qidi Zhai,
Zhisheng Guo,
Yibo Li,
Zhentao Tang,
Pan Zang,
Chenbo Ni,
Shaobo Zhang,
Jian Qian,
Peng Han,
Pu Li,
Pengfei Shao,
Chao Liang,
Jie Li
Affiliations
Qian Zhang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Urology, Jiangsu Taizhou People’s Hospital, Taizhou 225300, China
Lei Ding
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Ye Yan
Department of Urology, Peking University Third Hospital, Haidian District, Beijing, People’s Republic of China
Qidi Zhai
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Zhisheng Guo
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Yibo Li
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Zhentao Tang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Pan Zang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Chenbo Ni
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Shaobo Zhang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Jian Qian
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Peng Han
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Pu Li
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Pengfei Shao
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding author
Chao Liang
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding author
Jie Li
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding author
Summary: Sunitinib, a primary treatment for clear cell renal cell carcinoma (ccRCC), frequently encounters the challenge of resistance development. Metabolic reprogramming, a characteristic change in ccRCC, is likely linked to this resistance. Our research revealed a notable decrease in the expression of the key metabolic gene ABAT in ccRCC, which contributed to diminished sensitivity to sunitinib. Downregulation of ABAT led to an increase in the intracellular level of gamma-aminobutyric acid (GABA), triggering abnormal activation of the G-protein-coupled receptor GABA-B. This activation resulted in increased transactivation of the tyrosine kinase receptors SYK and LYN, thereby reducing the antitumor and antiangiogenic properties of sunitinib. However, the application of SYK and LYN inhibitors successfully inhibited this effect. The transactivation of SYK and LYN caused resistance to the antiangiogenic effects of sunitinib through the upregulation of PGF protein levels. Furthermore, the combined application of an LYN inhibitor with sunitinib has been shown to enhance therapeutic efficacy.
