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The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells

Zilu Wang1,2, Huimin Hu1,2, Luuk Heitink1,2

  • 1The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.

Cell Death and Differentiation
|February 4, 2023
PubMed

Insights

APR-246 kills cancer cells regardless of TP53 status, inducing apoptosis, necroptosis, and ferroptosis. This suggests broader clinical applications beyond mutant TP53 cancers, including wild-type or TP53-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mutant TP53 proteins are implicated in cancer development and progression by losing wild-type (wt) TP53 tumor suppressive functions.
  • APR-246 is an investigational compound designed to restore wt TP53 functions in mutant TP53 proteins, potentially inhibiting tumor expansion.
  • Emerging evidence suggests APR-246 may also affect malignant cells lacking mutant TP53, necessitating a deeper understanding of its mechanisms.

Purpose of the Study:

  • To investigate the mechanism of action of APR-246.
  • To determine if APR-246's efficacy is dependent on the TP53 mutational status of cancer cells.
  • To explore the potential of APR-246 in a broader range of cancer types.

Main Methods:

  • Establishment of isogenic background tumor cell lines with varying TP53/TRP53 states (wild-type, mutant, knockout).
  • RNA sequencing (RNAseq) analysis of Eμ-Myc mouse lymphoma cells treated with APR-246 across all four TRP53 states.
  • Assessment of programmed cell death pathways (apoptosis, necroptosis, ferroptosis) induced by APR-246.

Main Results:

  • APR-246 demonstrated efficacy in killing malignant cells irrespective of their TP53/TRP53 status.
  • RNAseq analysis revealed consistent gene set induction by APR-246 across all TRP53 states in Eμ-Myc lymphoma cells.
  • APR-246 induced programmed cell death via apoptosis, necroptosis, and ferroptosis, with sensitivity varying by cancer cell type and APR-246 concentration.

Conclusions:

  • APR-246 exhibits anti-cancer activity independent of TP53 mutational status.
  • The compound's mechanism involves the induction of multiple programmed cell death pathways.
  • Clinical trials for APR-246 should be expanded to include cancers with wild-type TP53 or those that are TP53-deficient, not solely mutant TP53 cancers.

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