Amplicon structure creates collateral therapeutic vulnerability in cancer

Summary Although DNA amplifications in cancers frequently harbor passenger genes alongside oncogenes, the functional consequence of such co-amplifications and their impact for therapy remains ill-defined. We discovered that passenger co-amplifications can create amplicon structure-specific collateral vulnerabilities. We present the DEAD-box helicase 1 ( DDX1 ) gene as a bona fide passenger co-amplified with MYCN in cancers. Survival of cancer cells with DDX1 co-amplifications strongly depends on the mammalian target of rapamycin complex 1 (mTORC1). Mechanistically, aberrant DDX1 expression inhibits the tricarboxylic acid cycle through a previously unrecognized interaction with dihydrolipoamide S-succinyltransferase, a component of the alpha-ketoglutarate dehydrogenase complex. Cells expressing aberrant DDX1 levels compensate for the metabolic shift by enhancing mTORC1 activity. Consequently, pharmacological mTORC1 inhibition triggered cell death specifically in cells harboring the DDX1 co-amplification. This work highlights a significant contribution of passenger gene alterations to the therapeutic susceptibility of cancers. Graphical abstract