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

Wang, Zilu; Hu, Huimin; Heitink, Luuk; Rogers, Kelly; You, Yue; Tan, Tao; Suen, Connie Li Wai; Garnham, Alex; Chen, Hao; Lieschke, Elizabeth; Diepstraten, Sarah T; Chang, Catherine; Chen, Tianwei; Moujalled, Diane; Sutherland, Kate; Lessene, Guillaume; Sieber, Oliver M; Visvader, Jane; Kelly, Gemma L; Strasser, Andreas

Author(s): Wang, Zilu; Hu, Huimin; Heitink, Luuk; Rogers, Kelly; You, Yue; Tan, Tao; Suen, Connie Li Wai; Garnham, Alex; Chen, Hao; Lieschke, Elizabeth; Diepstraten, Sarah T; Chang, Catherine; Chen, Tianwei; Moujalled, Diane; Sutherland, Kate; Lessene, Guillaume; Sieber, Oliver M; Visvader, Jane; Kelly, Gemma L; Strasser, Andreas;
Details: Publication Year 2023-02-04,Volume 30,Issue #4,Page 1033-1046
Journal Title: Cell Death & Differentiation
Abstract: Mutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through the loss of the wild-type (wt) TP53 tumour suppressive functions. Therefore, compounds that can restore wt TP53 functions in mutant TP53 proteins are expected to inhibit the expansion of tumours expressing mutant TP53. APR-246 has been reported to exert such effects in malignant cells and is currently undergoing clinical trials in several cancer types. However, there is evidence that APR-246 may also kill malignant cells that do not express mutant TP53. To support the clinical development of APR-246 it is important to understand its mechanism(s) of action. By establishing isogenic background tumour cell lines with different TP53/TRP53 states, we found that APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. Accordingly, RNAseq analysis revealed that treatment with APR-246 induces expression of the same gene set in Eμ-Myc mouse lymphoma cells of all four possible TRP53 states, wt, wt alongside mutant, knockout and knockout alongside mutant. We found that depending on the type of cancer cell and the concentration of APR-246 used, this compound can kill malignant cells through induction of various programmed cell death pathways, including apoptosis, necroptosis and ferroptosis. The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.
Publisher: NPG
Research Division(s): Bioinformatics; Chemical Biology; Personalised Oncology; Structural Biology; Advanced Technology And Biology; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells; Epigenetics And Development; Population Health And Immunity
PubMed ID: 36739334/
Publisher's Version: https://doi.org/10.1038/s41418-023-01122-3
Open Access at Publisher's Site: https://doi.org/10.1038/s41418-023-01122-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41418-023-01122-3.pdf - (5.56MB, application/pdf)

Creation Date: 2023-03-08 03:16:11

Last Modified: 2023-04-12 09:57:32