LAUSR

Simple Summary ETS transcription factors are potent oncogenic drivers in several cancer types and represent promising therapeutic targets. However, molecular factors influencing response to ETS factor inhibition are widely unknown so far. Here, we uncover that sensitivity of cancer cells against ETS factor blockade by the small molecule inhibitor YK-4-279 is strongly promoted by p53 loss in a MAPK-driven background. Induction of a parthanatos-like cell death based on a deregulated MAPK/ETS1/p53/PARP1 signal axis is identified as underlying molecular mechanism. Hence, this study suggests a novel and biomarker-driven therapeutic strategy for p53-deleted tumours, generally known for their profound therapy resistance. Abstract The small-molecule E26 transformation-specific (ETS) factor inhibitor YK-4-279 was developed for therapy of ETS/EWS fusion-driven Ewing’s sarcoma. Here we aimed to identify molecular factors underlying YK-4-279 responsiveness in ETS fusion-negative cancers. Cell viability screenings that deletion of P53 induced hypersensitization against YK-4-279 especially in the BRAFV600E-mutated colon cancer model RKO. This effect was comparably minor in the BRAF wild-type HCT116 colon cancer model. Out of all ETS transcription factor family members, especially ETS1 overexpression at mRNA and protein level was induced by deletion of P53 specifically under BRAF-mutated conditions. Exposure to YK-4-279 reverted ETS1 upregulation induced by P53 knock-out in RKO cells. Despite upregulation of p53 by YK-4-279 itself in RKOp53 wild-type cells, YK-4-279-mediated hyperphosphorylation of histone histone H2A.x was distinctly more pronounced in the P53 knock-out background. YK-4-279-induced cell death in RKOp53-knock-out cells involved hyperPARylation of PARP1, translocation of the apoptosis-inducible factor AIF into nuclei, and induction of mitochondrial membrane depolarization, all hallmarks of parthanatos. Accordingly, pharmacological PARP as well as BRAFV600E inhibition showed antagonistic activity with YK-4-279 especially in the P53 knock-out background. Taken together, we identified ETS factor inhibition as a promising strategy for the treatment of notoriously therapy-resistant p53-null solid tumours with activating MAPK mutations.