Related Experiment Video

Updated: Feb 5, 2026

Methods to Inhibit Bacterial Pyomelanin Production and Determine the Corresponding Increase in Sensitivity to Oxidative Stress
11:00

Methods to Inhibit Bacterial Pyomelanin Production and Determine the Corresponding Increase in Sensitivity to Oxidative Stress

Published on: August 31, 2015

8.7K

Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in

Na Li1,2, Michael A Lopez1, Maria Linares3

  • 1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 13, 2018
PubMed
Abstract

Insights

p21-activated kinase 4 (PAK4) is highly expressed in Waldenström's macroglobulinemia (WM) cells. A dual PAK4-NAMPT inhibitor, KPT-9274, effectively reduces WM cell growth and viability by inducing apoptosis and DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • p21-activated kinase 4 (PAK4) is implicated in various cancers, including multiple myeloma (MM).
  • Understanding PAK4's role in Waldenström's macroglobulinemia (WM) is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate PAK4 expression and function in WM cells.
  • To evaluate the efficacy of the dual PAK4-NAMPT inhibitor KPT-9274 against WM cells in vitro and in vivo.

Main Methods:

  • Analysis of PAK4 mRNA and protein expression in WM cells.
  • Loss-of-function studies using shRNA to assess PAK4's role in WM cell viability.
  • In vitro and in vivo testing of KPT-9274 efficacy.
  • Assessment of DNA damage and repair pathways following KPT-9274 treatment.
  • Combination studies with DNA alkylating agents (bendamustine, melphalan).

Main Results:

  • High-level expression and functional significance of PAK4 were confirmed in WM cells.
  • KPT-9274 significantly inhibited WM cell growth and viability, decreasing PAK4 expression and NAMPT activity, and inducing apoptosis.
  • KPT-9274 treatment impacted DNA damage and repair genes, specifically reducing RAD51 and homologous recombination-mediated double-strand break repair.
  • Synergistic inhibition of cell viability was observed when KPT-9274 was combined with bendamustine or melphalan in WM cell lines and primary patient cells.

Conclusions:

  • PAK4 plays a critical role in WM pathogenesis.
  • KPT-9274 demonstrates significant anti-WM activity, mediated through apoptosis induction and disruption of DNA repair pathways.
  • Combination therapy with KPT-9274 and DNA-damaging agents warrants clinical investigation for WM treatment.

More Related Videos

Demonstration of the DNA Fiber Assay for Investigating DNA Damage and Repair Dynamics Induced by Nanoparticles13:09

Demonstration of the DNA Fiber Assay for Investigating DNA Damage and Repair Dynamics Induced by Nanoparticles

Published on: March 3, 2023

5.1K
Evaluating In Vitro DNA Damage Using Comet Assay10:43

Evaluating In Vitro DNA Damage Using Comet Assay

Published on: October 11, 2017

39.6K

Related Concept Videos

DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.2K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.1K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.2K
Increasing Function01:18

Increasing Function

An increasing function exhibits a rise in output values as input values increase. This behavior is depicted graphically as a curve or line that slopes upward from left to right. Such a function satisfies the condition that if x1 < x2, then f(x1) < f(x2), indicating that the function values grow with increasing inputs. This concept is fundamental in understanding growth trends across various domains, such as population dynamics, financial investments, or resource consumption.The...
397
Survival Curves01:18

Survival Curves

Survival curves are graphical representations that depict the survival experience of a population over time, offering an intuitive way to track the proportion of individuals who remain event-free at each time point. These curves are widely used in fields such as medicine, public health, and reliability engineering to visualize and compare survival probabilities across different groups or conditions.
The Kaplan-Meier estimator is the most common method for constructing survival curves. This...
719
Survival Tree01:19

Survival Tree

Survival trees are a non-parametric method used in survival analysis to model the relationship between a set of covariates and the time until an event of interest occurs, often referred to as the "time-to-event" or "survival time." This method is particularly useful when dealing with censored data, where the event has not occurred for some individuals by the end of the study period, or when the exact time of the event is unknown.
 Building a Survival Tree
Constructing a...
433