Multimodal profiling unveils a reversible breast basal-like cell state in AKT-inhibitor resistant tumours

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, ΔNp63α, 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. Competing Interest Statement E.S. reports grants from Novartis, Merck Sharp Dohme, AstraZeneca and personal fees from Phenomic outside the submitted work. C.D. has a granted patent on oblique plane microscopy (OPM) (PCT/GB2009/001802) licensed to Leica Microsystems and sublicensed to ASI, and has filed a patent application (PCT/GB2020/052279) on dual-view oblique plane microscopy (dOPM). H.H., L.F., and S.T.B. are employees and shareholders of AstraZeneca. Footnotes Figures, Supplemental files, Text and authors have been updated.