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Jennifer R. Brown, MD, PhD

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Defining the Role of PAK1 in Ibrutinib-Resistant CLL

By: Lauren Harrison, MD, MS
Posted: Wednesday, September 7, 2022

Researchers from Nanjing Medical University in China described the oncogenic role of p21-activted kinase 1 (PAK1) in the progression of chronic lymphocytic leukemia (CLL) and development of resistance to the kinase inhibitor ibrutinib. Hui Jin, PhD, and colleagues published their findings in Molecular Oncology. “This result provides promising therapeutic targets for overcoming ibrutinib resistance. In particular, the treatment of CLL patients with a combination of IPA-3 and ibrutinib may improve clinical outcomes,” concluded the authors.

CLL cells resistant to ibrutinib were generated and compared with cells sensitive to the drug. Multiomic analysis revealed the basic structural units of the genome were stable in the ibrutinib-resistant cells; however, there were changes in these cells noted at the DNA, RNA, and protein levels. There were 110 dysregulated genes in the ibrutinib-resistant CLL cells. PAK1 was one of the genes that was highly upregulated in the resistant cell line.

Samples from patients with CLL were then analyzed using RNA sequencing, which demonstrated PAK1 upregulation as well as upregulation of BCAT1 genes. Higher expression levels of PAK1 associated with a worse overall survival and high-risk Rai stages. Functional assays suggested that PAK1 overexpression of PAK1 promoted cell proliferation, whereas knockdown led to a marked suppression in cell viability. PAK1 specifically suppressed the expression of proapoptotic proteins and promoted the expression of antiapoptotic proteins.

Peripheral bone marrow cell samples from patients with CLL were compared with healthy control group patients. In patients with CLL, PAK1 mRNA levels were significantly higher compared with those of the healthy control group. In addition, BCAT1 was also found to be upregulated in the CLL samples. Patients with higher PAK1 expression tended to have shorter overall survival. Although BCAT1 inhibitors showed no significant antitumor efficacy in CLL, the combined use of IPA-3 and BCAT1 inhibitors seemed to have a synergistic effect.

Disclosure: The authors reported no conflicts of interest.


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