Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Significance Emergence of resistance to targeted therapy constitutes a limitation to long-term clinical benefits in many instances. To anticipate potential mechanisms of resistance to double minute 2 protein (MDM2) inhibitors, we performed a piggyBac insertional mutagenesis screen in a cohort of allografts with an underlying CDKN2A deletion, in the presence and absence of the MDM2 inhibitor HDM201. Among the most frequent events conferring resistance, we found several mechanisms converging on direct or indirect loss-of-function inactivation of tumor protein 53 (TP53), as well as activation of the antiapoptotic B-cell lymphoma-extra large ( Bcl-xL ) gene. Importantly, our findings were confirmed in patient-derived xenograft models, underlining the benefit of large-scale in vivo forward genetic screening to identify potential resistance mechanisms to targeted therapeutics.