FOXA2 Promotes Prostate Cancer Lineage Plasticity through KIT

Cell lineage plasticity can mediate tumor progression as well as resistance to therapies, which is exemplified in the adeno (or luminal)-to-neuroendocrine lineage transition that occurs in prostate adenocarcinoma after androgen receptor (AR) inhibition. However, the dynamics and underlying mechanisms associated with this plasticity remain unknown. To systematically characterize the gene expression profiles, chromatin regulatory landscape, and microenvironmental factors that underlie prostate cancer lineage plasticity, Han, Li, Zhang, and colleagues generated a murine lineage tracing model (which included Pten, Trp53, and Rb1 deletion driven by the luminal cell–specific Tmprss2^CreERT2) and conducted single-cell multiomics of 107,201 cells. Results showed that the FOXA2 and FOXA1 transcription factors promote the PCa luminal-to-neuroendocrine transition, with FOXA2 showing the most prominent potential in late-stage neuroendocrine prostate cancer (NEPC) progression. Moreover, FOXA2 DNA binding activity was markedly increased during progression of NEPC, while FOXA1 DNA binding activity decreased, suggesting that FOXA2 preferentially promotes neuroendocrine differentiation and suppresses the luminal lineage. FOXA2 was also functionally associated with chromatin remodeling, with its expression and binding activity being supported by androgen deprivation, while FOXA1 contrarily responded to AR inhibition. Loss of FOXA2 expression induced the reversal of the adeno-to-neuroendocrine lineage transition, and mechanistically, FOXA2 was found to increase Kit expression, with the KIT signaling pathway being heavily involved in cell–cell communication and induction of cell proliferation, suggesting its critical role in promoting NEPC progression. Inhibition of the KIT pathway reduced NEPC tumor growth in vivo, with similar results being observed after treatment with the KIT tyrosine kinase inhibitor imatinib as well as other KIT inhibitors. In conclusion, this study demonstrates that the FOXA2 transcription factor drives the luminal-to-neuroendocrine transition observed in prostate cancer after AR inhibition and suggests that targeting KIT downstream of FOXA2 could provide therapeutic benefit in NEPC.

Han M, Li F, Zhang Y, Dai P, He J, Li Y, et al. FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer. Cancer Cell 2022;40:1306–23.e8.

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