Background
The response of cancer cells to treatment is highly heterogeneous, ranging from sensitivity to tolerance, to outright resistance. While the initial response of tumours to treatment is often robust, their incomplete eradication often leads to relapse. Survival during the acute response phase is the first essential step for cancer on the path to relapse and resistance. This short period of time largely precludes the acquisition of genetic changes from facilitating survival and thus relies upon the adaptability of individual cells. Identifying which of these cells exhibit differential tolerance to acute treatment and the properties that enable their acute survival may reveal novel mechanisms of relapse that can be addressed.
Methodology
A Polyclonal and single-cell clone-derived population of acute myeloid leukaemia (AML) cells were barcoded using the Watermelon DNA barcode library. The same barcoded population of cells was then split and treated with a range of therapies targeting different core cellular functions: Venetoclax (apoptosis), Gilteritinib (signalling), Menin inhibitor (epigenetics), or Cytarabine (chemotherapy). The cells were treated for 20 days, or 10 days followed by a 10-day drug withdrawal with samples harvested periodically.
Results
We found that the response of both polyclonal and clonally derived AML cells differed between the different classes of therapy but that the fate of cell lineages was highly concordant across replicates of the same treatment. This suggests that lineage properties are heritable and can inform the reproducible response to specific treatment. Furthermore, the heterogeneity of response between lineages within each treatment condition was apparent in the clear stratification of sensitive, tolerant, and ‘resistant’ lineages. Interestingly, while the response to each class of therapy was distinct, there were select lineages that exhibited pan-tolerance (and pan-sensitivity) to treatment. This heterogeneity creates a spectrum of responses to treatment, enabling subsets of lineages to persist and potentially seed relapse.