Multimodal profiling unveils a reversible basal-like breast cancer cell state resistant to AKT inhibition
Ratcliffe, C. D. H.; Sparks, H.; Boezio, G. L. M.; Alexandrov, Y.; Jenkins, R. P.; Le Marois, A.; Soro-Barrio, P.; Lee, R.; Strohbuecker, S.; Joshi, S.; Ellis, J. K.; Fortier, A.-M.; Gustafsson, N.; Cunha, A. C.; Park, M.; MacRae, J. I.; Serio, A.; Briscoe, J.; Riddell, A.; Barry, S. T.; Dunsby, C.; Sahai, E.
Show abstract
The PI3K/AKT/mTOR pathway is central to cell metabolism and growth. However, pharmacological inhibition of the pathway is not uniformly effective across cancer types, or even within a single cancer model. In this study, we leverage oblique plane microscopy of triple negative breast cancer organoids, as well as lineage tracing to uncover a source of heterogeneity. Non-genetic resistance to AKT inhibition is associated with basal cell features of normal breast epithelium and the master transcription factor of basal cell state, {Delta}Np63, is sufficient to confer resistance. Cells can transition between states within four weeks and therefore, AKT inhibition only delays tumour growth, with tumours rich in KRT14+ cells resulting. Thus, under selection, triple negative breast cancer exploits a repertoire of cell states inherent to the breast.
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