Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

Abstract

The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors.

Cellular and molecular mechanisms of plasticity in cancer

“…This suggests that only a subset of the cancer cells harbors the capacity for neuroendocrine transformation. In line with this, both prostate cancer [89] and LUAD [90] contain cell states that develop lineage infidelity under therapeutic pressure. In response to immunotherapy, PDAC cells undergo a phenotypic shift from a classical transcriptional state to a highly plastic intermediate state [46].…”

“…Other therapeutically actionable signaling pathways that drive plasticity are emerging. Targeting JAK/STAT and FGFR signaling is promising for suppressing neuroendocrine transformation in prostate cancer [89]. Furthermore, a highly plastic cell state in small cell lung cancer depends on the activity of phospholipase-Cγ2 [94].…”

Phenotypic Plasticity - Alternate Transcriptional Programs Driving Treatment Resistant Prostate Cancer

“…34,35 Another recent study by Karthaus et al found that co-deletion of tumor suppressor genes Rb1/Trp53 by lentiviral transduction of prostate organoids also led to a lineage plastic phenotype as evident from reduced expression of luminal lineage genes such as Nkx3.1, Folh1, Dpp4, Krt18, and Krt8 but increased expression of mesenchymal genes such as Zeb2, Vim, and Snai1. 36 Single-cell RNA-sequencing using organoids from these GEM models showed EMT (SMAD2 signature), Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and fibroblast growth factor receptor (FGFR) signaling as top candidate pathways driving lineage plasticity in these prostate cancer models. 36 A parallel study led by Deng et al using LNCaP/AR cell lines with loss of TP53/RB1, TP53/RB1/SOX2 and SOX2 overexpression, and Rb1:Tp53 mouse organoids shows that JAK-STAT signaling can promote LP-PCa and EMT phenotype.…”

“…36 Single-cell RNA-sequencing using organoids from these GEM models showed EMT (SMAD2 signature), Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and fibroblast growth factor receptor (FGFR) signaling as top candidate pathways driving lineage plasticity in these prostate cancer models. 36 A parallel study led by Deng et al using LNCaP/AR cell lines with loss of TP53/RB1, TP53/RB1/SOX2 and SOX2 overexpression, and Rb1:Tp53 mouse organoids shows that JAK-STAT signaling can promote LP-PCa and EMT phenotype. 37 Specifically loss of TP53/RB1 results in over expression of SOX2 in prostate cancer cells, and activates reprograming of H3K27ac, H3K27me3, and H3K4me3 gene targeting resulting in activation of JAK1, implicating JAK-STAT signaling as a potential target for treatment of LP-PCa.…”