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.