Prostate cancer

JAK inhibition shows two faces in prostate cancer

Therapeutic resistance in prostate cancer can be driven by lineage plasticity, but the mechanisms behind this are unclear, and therapies to prevent or reverse the process are nonexistent. A new study reveals the JAK/STAT signaling axis as a driver of lineage plasticity with tremendous therapeutic potential.

Over the past decade, advances in the mechanistic understanding of prostate cancer biology have led to significant improvements in patient survival. Although nearly all patients with advanced prostate cancer initially respond to therapies targeting androgen receptor (AR) signaling, castration-resistant prostate cancer (CRPC) resistant to these therapies frequently develops. Most resistant tumors remain dependent on the AR signaling pathway through a variety of genomic and epigenetic mechanisms, including AR gene amplification, mutations and splice variants. However, nearly 40% of CRPC tumors display evidence of transitioning away from an AR-dependent phenotype toward alternative lineage programs1. These AR-independent tumors are further subcategorized into distinct phenotypes, including neuroendocrine prostate cancer (NEPC), double-negative prostate cancer (DNPC) and intermediate phenotypes. Shared genomic alterations between NEPC and prostate adenocarcinoma indicate that NEPC tumors arise clonally from adenocarcinoma during treatment and that significant epigenetic deregulation occurs during the transition process2,3,4. With the increased use of more potent AR-targeted therapies in the past decade, the emergence of AR-negative tumors during the course of treatment has more than tripled (from 11.7% to 36.6%)1. Many studies have identified potential drivers of this transition to androgen independence, including loss of CHD15,6, concurrent loss of TP53 and RB17, and upregulation of MYCN8,9, EZH210, BRN211 and SOX212. Although these have been nominated as drivers of lineage plasticity and NEPC, there is still much to learn about the molecular and genomic changes that promote the acquisition of the AR-indifferent phenotypes, the progression of prostate adenocarcinoma cells to androgen independence following AR-targeted therapies, and the hierarchical and temporal relationships among different cell populations.