PEBP1 is a candidate biomarker of response to the PP2A inhibitor LB-100

We recently proposed an approach for cancer therapy involving a “paradoxical” activation of oncogenic signaling combined with the inhibition of stress responses. However, as with any other treatment, resistance can also emerge with hyperactivation therapy. In this study, we explored how cancer cells can acquire resistance to a drug that hyperactivates oncogenic signaling using the Protein Phosphatase 2A (PP2A) LB-100 as an example. Our findings indicated that PEBP1 depletion confers resistance to LB-100 in different cancer models. Mechanistically, resistance is mediated by a reduced conversion of the prodrug LB-100 into the active metabolite endothall in the absence of PEBP1. Our data are compatible with a model in which PEBP1 is a hydrolase that can convert the prodrug LB-100 into the active endothall.