Research; Prostate Cancer

Preventing Lineage Plasticity in Prostate Cancer Cells Resensitizes Them to Therapy

Research; Prostate Cancer

UTSW study suggests combination therapy might help prostate cancer patients overcome resistance to AR-targeted therapy.

Recent evidence suggests that various cancers can acquire resistance to targeted therapies by gaining lineage plasticity. While various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated.

A new study, led by Ping Mu, Ph.D., Assistant Professor of Molecular Biology at UT Southwestern, has revealed that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a key promotor of lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer.

“In metastatic castration-resistant prostate cancer [mCRPC], several mechanisms have been shown to confer resistance to AR-targeted therapy,” Dr. Mu says. “One such mechanism, called lineage plasticity, may result in cells transitioning to a stem like and multilineage state, conferring AR-targeted therapy resistance.”

In previous studies, lineage plasticity was observed in mCRPC and characterized by various genomic and transcriptional aberrations, which parallels other examples in EGFR-mutant lung cancer, estrogen receptor (ER)-positive breast cancers, and BRAF-mutant melanoma, Dr. Mu explains. In new research published in Nature Cancer, he and his co-investigators elucidated the molecular mechanism promoting lineage plasticity in many mCRPC subtypes, providing unique insight into potential therapeutic targets to overcome lineage plasticity-driven AR-targeted therapy resistance.

“Therapeutic approaches targeting lineage plasticity-driven resistance are not currently available, underscoring the unmet clinical urgency to identify druggable targets that drive lineage plasticity,” Dr. Mu explains.

“JAK-STAT signaling appears to be a crucial executor driving lineage plasticity and could be a potential therapeutic target designed to overcome AR-targeted therapy resistance.”

Ping Mu, Ph.D.

The JAK-STAT Signaling Pathway

After completion of genomic and transcriptomic analyses, Dr. Mu and his team found that the ectopic activation of JAK-STAT signaling is required for lineage plasticity-driven AR-targeted therapy resistance in mCRPC with TP53/RB1 deficiency and SOX2 upregulation. In addition, single-cell RNA-sequencing (scRNA-seq) analysis revealed that JAK-STAT signaling is specifically required for AR therapy resistance of subclones expressing stem like and multilineage transcriptional programs, although not for AR therapy resistance of subclones exclusively expressing the neuroendocrine (NE)-like lineage program.

“These findings demonstrate that both genetic and pharmaceutical inactivation of key components of the JAK-STAT pathway, including JAK1/JAK2 and STAT1/STAT3, resensitize resistant mCRPC to AR-targeted therapy,” Dr. Mu says. “JAK-STAT signaling appears to be a crucial executor driving lineage plasticity and could be a potential therapeutic target designed to overcome AR-targeted therapy resistance.”

Clinical Implications

While lineage plasticity has been suggested as a key mechanism conferring resistance, effective therapeutic approaches targeting lineage plasticity are still not available. Dr. Mu hypothesizes that various pharmaceutical inhibitors targeting different JAK and STAT proteins could have combinatorial effects when administered with enzalutamide.

Despite the clinical success of AR-targeted therapies, resistance to these therapies universally occurs and largely impairs the clinical outcome of individuals with mCRPC. Dr. Mu believes these results provide a rationale for future clinical trials designed to target JAK-STAT signaling for overcoming lineage plasticity-driven AR-targeted therapy resistance.

On the basis of these results, Dr. Mu and his collaborators are planning a clinical trial to determine whether JAK-STAT inhibitors can help in this regard. “We are trying to utilize small molecule inhibitors that were originally developed to target the JAK-STAT pathway,” he says. “It’s very exciting but still early days for testing it; there is much more that this lineage plasticity story has yet to reveal.”

Ping Mu, Ph.D., is an Assistant Professor of Molecular Biology at UT Southwestern and a member of the Development and Cancer Program at Simmons Cancer Center. His research is focused on identifying a novel mechanism of AR-targeted therapy resistance in prostate cancer mediated by increased lineage plasticity, or “identity fraud.”

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