Simultaneous JAK/FGFR Inhibition Restores Anti-AR Sensitivity in CRPC

Lineage plasticity is well recognized as a method of drug resistance across many unique cancer types but in general remains poorly characterized. In order to fully understand plasticity as a method of therapeutic escape, it is critical to profile identity changes that arise alongside resistance. To thoroughly characterize prostate cancer tumor evolution during anti–androgen receptor (AR) therapy resistance, Chan, Zaidi, and colleagues used genetically engineered mouse models and organoids and found that tumor-intrinsic JAK/STAT inflammatory signaling drives the emergence of a hyperplastic cellular state insensitive to anti-AR therapy. In a mouse model of prostate cancer driven by the deletion of Pten, Rb, and Trp53, single-cell RNA sequencing (scRNA-seq) was performed throughout tumor development to capture progression into two castration-resistant prostate cancer (CRPC) phenotypes—adenocarcinoma (CRPC-adeno) and neuroendocrine prostate cancer (NEPC)—and indicated that CRPC-adeno emerges earlier in tumor development than NEPC and is identified as the most likely source of enhanced plasticity. To determine if this plasticity is cell autonomous or dependent on the tumor microenvironment, organoid cultures were evaluated, with normal prostate epithelial organoids maintaining a luminal identity, but, upon deletion of Trp53 and Rb1, organoids became hyperplastic. This recapitulated early plasticity in vivo and suggests that progression into plasticity is a cell-intrinsic phenotype. Identification of gene programs associated with early plasticity that were enriched after anti-AR therapy revealed that the JAK/STAT pathway was strikingly upregulated in plastic cell populations, with particular enrichment for autocrine signaling via the FGF1/FGFR ligand–receptor pair. This signature was also observed using human scRNA-seq data as well as patient-derived CRPC organoids. Functional testing using both genetic and pharmacologic methods to inhibit FGFR and JAK1/2 signaling demonstrated that simultaneously targeting both pathways in hyperplastic cells causes reversion to a more luminal-like state as well as robustly restores sensitivity to anti-AR therapy. Altogether, this work comprehensively profiles the evolution of lineage plasticity that drives castration resistance in prostate cancer and identifies novel therapeutic vulnerabilities for a subset of CRPC.

Chan JM, Zaidi S, Love JR, Zhao JL, Setty M, Wadosky KM, et al. Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. Science 2022;377:1180–91.

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