A Proteome-Wide Gain-of-Function Atlas Mapping the Landscape of Chemotherapy Response

A proteome-wide gain-of-function screen in HeLa cells mapped 230,000+ gene–drug interactions, showing TAS-102 (Lonsurf) converges on a BCL-2–linked autophagy-endolysosomal survival hub.

• Why it matters: Chemoresistance limits conventional chemotherapy, yet reference maps have focused mainly on loss-of-function, leaving gain-of-function mechanisms that drive resistance insufficiently charted.
• What they did: Using a Bxb1 integrase landing-pad system, the study integrated 18,388 ORFs at AAVS1 and profiled fitness across 16 chemotherapeutics, then combined RNA-seq, FACS lysosomal assays, clinical survival analyses, and xenograft modeling.
• The result: TAS-102 activated lysosomal function as an adaptive survival response, and ABT-263 (Navitoclax) co-treatment attenuated this response and synergistically reversed TAS-102 resistance in colorectal and pancreatic models in vitro and in colorectal CDX/PDX in vivo.

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