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

Abstract

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.

m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia

“…[ 37 ] We have previously reported the upregulation of mROTC1‐related proteins in CLL patients, especially those with refractory or relapsed disease. [ 38 ] With the treatment of the dual ATP‐competitive PI3K and mTOR inhibitor dactolisib, the proliferative ability of CLL cells was observed to be significantly impaired. In addition, the expression of CPT1A was also reduced.…”

“…Clinical Samples, Cell Lines, and Reagents: Peripheral blood mononuclear cells (PBMCs) from CLL patients were collected and wholetranscriptome sequencing was performed as previously reported. [38] The CLL cell lines MEC-1 and JVM-3, human B lymphocyte cell lines GM12878 and NCI-BL2009, DLBCL cell lines SU-DHL-10 and WSU-DLCL2, T cell lymphoma cell lines H9 and MT4, CML cell line K562, and monocytic leukemia cell line THP1 were used in this study and cultured in RPMI-1640 with 10% FBS (BioChannel Biological Technology) and 1% PS (Gibco), and cell transfection was performed as previously reported. [41] We purchased short hairpin RNAs and overexpression vectors from Genechem (Shanghai, China).…”

“…Seahorse Assay: Oxygen consumption rate (OCR) was measured using a Seahorse XFe96 Analyzer (Seahorse Bioscience, Agilent Technologies, Santa Clara, CA, USA) as previously reported. [38] The experiment was performed with three biological replicates, and data were expressed as the mean ± SD. Two-way ANOVAs and t-tests were used to perform statistical analysis.…”

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

“…Wu et al, [64] through their high-throughput chromosome conformation capture (Hi-C) technology and multiomic approach, discovered that PAK1 plays a pivotal role in resistance to ibrutinib. In CLL, PAK1 inhibitor IPA-3 inhibited cell proliferation, and its combination with ibrutinib resulted in a synergistic effect in ibrutinib-sensitive and -resistant cells, revealing its role in drug resistance [65].…”