Exploring the significance of PAK1 through chromosome conformation signatures in ibrutinib‐resistant chronic lymphocytic leukaemia

• Published in: Molecular oncology 2022-08, Vol.16 (16), p.2920-2935
• Main Authors: Wu, Zijuan, Wang, Luqiao, Fan, Lei, Tang, Hanning, Zuo, Xiaoling, Gu, Danling, Lu, Xueying, Li, Yue, Wu, Jiazhu, Qin, Shuchao, Xia, Yi, Zhu, Huayuan, Wang, Li, Xu, Wei, Li, Jianyong, Jin, Hui
• Format: Article
• Language: English
• Subjects: Acidification; Analysis; Apoptosis; B cells; Cell growth; Cell proliferation; Cell survival; Chromosomes; chronic lymphocytic leukaemia; Chronic lymphocytic leukemia; Conformation; Drug resistance; Ethylenediaminetetraacetic acid; Experiments; Genomes; Genomics; Glycolysis; Health aspects; ibrutinib resistance; Kinases; Leukemia; metabolism; Molecular modelling; Mutation; Oxidative phosphorylation; PAK1; Phosphorylation; Therapeutic targets; three‐dimensional genome; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13281

Ibrutinib exerts promising anticancer effects in chronic lymphocytic leukaemia (CLL). However, acquired resistance occurs during treatment, necessitating the exploration of underlying mechanisms. Although three‐dimensional genome organization has been identified as a major player in the development and progression of cancer, including drug resistance, little is known regarding its role in CLL. Therefore, we investigated the molecular mechanisms underlying ibrutinib resistance through multi‐omics analysis, including high‐throughput chromosome conformation capture (Hi‐C) technology. We demonstrated that the therapeutic response to ibrutinib is associated with the expression of p21‐activated kinase 1 (PAK1). PAK1, which was up‐regulated in CLL and associated with patients' survival, was involved in cell proliferation, glycolysis and oxidative phosphorylation. Furthermore, the PAK1 inhibitor IPA‐3 exerted an anti‐tumour effect and its combination with ibrutinib exhibited a synergistic effect in ibrutinib‐sensitive and ‐resistant cells. These findings suggest the oncogenic role of PAK1 in CLL progression and drug resistance, highlighting PAK1 as a potential diagnostic marker and therapeutic target in CLL including ibrutinib‐resistant CLL. The oncogene PAK1 was found located in a region where B‐to‐A compartment switching occurred in established ibrutinib‐resistant CLL cells. PAK1 regulated the oxidative phosphorylation and glycolysis of CLL cells, promoted cell proliferation and affected the sensitivity to ibrutinib.