CDK1 inhibitor RO-3306 enhances BTKi potency in diffuse large B-cell lymphoma by suppressing JAK2/STAT3 signaling.

in International journal of biological macromolecules by Qiuni Chen, Chuanyang Lu, Dongnan Li, Lei Xu, Chunling Wang, Liang Yu

TLDR

  • A study elucidated the key genes influencing sensitivity to Bruton's tyrosine kinase inhibitors (BTKi) in diffuse large B-cell lymphoma (DLBCL) and identified cyclin-dependent kinase 1 (CDK1) as a central gene regulating BTKi sensitivity
  • CDK1 inhibition increased the growth and apoptotic rate of DLBCL cells and made them more susceptible to BTKis in in vitro and in vivo experiments
  • The study may lead to the development of novel targeted therapies for refractory DLBCL patients

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, which characterized by a high degree of heterogeneity in terms of clinical presentation, molecular phenotype, and genetic features. However, approximately 30 %-40 % of patients are refractory to standard chemotherapy, and their prognosis is poor. The emergence of small-molecule inhibitors, such as Bruton's tyrosine kinase inhibitors (BTKi), has greatly improved the treatment of DLBCL; however, drug resistance associated with small-molecule inhibitors has greatly limited their clinical application. In this study, we elucidated the principal genes influencing BTKi sensitivity in DLBCL and delineated the underlying mechanisms. This study identified cyclin-dependent kinase 1 (CDK1) as the central gene influencing BTKi sensitivity in DLBCL cells. The application of RO-3306 effectively promoted the growth and increased the apoptotic rate of DLBCL cells. Furthermore, RO-3306 increased the susceptibility of DLBCL cells to BTKis in both in vitro and xenograft experimental models. RNA-seq analyses suggested the potential modulation of the JAK2/STAT3 signaling cascade by RO-3306, a finding further confirmed by the diminished phosphorylation documented by western blotting. This study provides pivotal insights into the mechanisms governing BTKi sensitivity in DLBCL and potentially reveals new avenues for targeted therapeutic strategies.

Overview

  • The study aimed to identify the principal genes influencing the sensitivity of DLBCL cells to small-molecule inhibitors, particularly Bruton's tyrosine kinase inhibitors (BTKi)
  • Cyclin-dependent kinase 1 (CDK1) was identified as the central gene influencing BTKi sensitivity in DLBCL cells, which is crucial for understanding the mechanisms behind BTKi resistance
  • The study employed in vitro and in vivo experiments to elucidate the roles of CDK1 and its potential targets in BTKi resistance

Comparative Analysis & Findings

  • The study found that the application of RO-3306, a CDK1 inhibitor, increased the growth and apoptotic rate of DLBCL cells, suggesting its potential as a therapeutic strategy
  • RO-3306 increased the susceptibility of DLBCL cells to BTKis in both in vitro and xenograft experimental models, which may improve treatment outcomes for refractory DLBCL patients
  • RNA-seq analyses suggested that RO-3306 modulated the JAK2/STAT3 signaling cascade, which was confirmed by western blotting

Implications and Future Directions

  • This study may lead to the development of novel targeted therapies for DLBCL patients resistant to standard chemotherapy, potentially improving treatment outcomes and survival rates
  • Future studies can investigate the combination of CDK1 inhibitors with BTKis to enhance therapeutic efficacy and overcome BTKi resistance mechanisms
  • The identification of CDK1 as a key regulator of BTKi sensitivity may inform the development of biomarkers for predicting treatment response and monitoring therapeutic outcomes
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