Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells

Even amongst genetically identical cancer cells, therapy resistance often only emerges from a small subset of cells. However, comparatively little is known about variability in the resistant outcomes and its origins. Here, we combined DNA barcoding with single-cell RNA sequencing to reveal the fates of thousands of clones exposed to anti-cancer therapies. We showed that resistant clones emerging from single-cell-derived cancer cells adopt molecularly and functionally distinct fate types. Different resistant types were predetermined by molecular differences between single cells before drug addition. Changes in dose and kind of drug can, however, switch the resistant fate type of an initial cell, resulting in the generation and elimination of certain fates. Diversity in resistant fates appeared across several single-cell-derived cancer types and drug treatments. Cell fate diversity arising from variability in intrinsic cell states may be a generic feature of response to external cues.