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.

doi:10.1101/2025.06.06.658331

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bioRxiv · 10.1101/2025.06.06.658331

Multimodal profiling unveils a reversible basal-like breast cancer cell state resistant to AKT inhibition

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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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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.. 2025-06-07. Multimodal profiling unveils a reversible basal-like breast cancer cell state resistant to AKT inhibition. https://doi.org/10.1101/2025.06.06.658331

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