Understanding Resistance to PSMA-Targeted Therapy

Emerging research is shedding light on the molecular mechanisms driving resistance to lutetium Lu 177 vipivotide tetraxetan (Pluvicto), a targeted radioligand therapy approved for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Jacob E. Berchuck, MD, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, highlights novel findings pointing to androgen receptor (AR) signaling and Wnt pathway activation as key correlates of poor response to therapy.

According to Berchuck, one of the initial observations was related to PSMA expression, which is essential for lutetium Lu 177 vipivotide tetraxetan targeting. However, more nuanced molecular signals have now come into focus. A particularly compelling discovery was that patients whose tumors showed higher AR signaling activity experienced worse outcomes with lutetium Lu 177 vipivotide tetraxetan.

“We think we are seeing the downstream effects of those activating genomic alterations, which lead to elevated AR signaling,” Berchuck explains in an interview with Targeted Oncology. “And higher AR activity seems to correspond with resistance to Pluvicto as well.”

Beyond AR signaling, researchers employed an unbiased transcriptomic approach to broadly examine pathways associated with treatment resistance. In doing so, they identified Wnt signaling as the pathway most strongly linked to poor outcomes. This finding is particularly noteworthy, as Wnt pathway activation is already known to confer poor prognosis in prostate cancer and has been implicated in resistance to other androgen receptor pathway inhibitors such as abiraterone (Zytiga) and enzalutamide (Xtandi).

“Wnt signaling is known to be associated with poor prognosis in prostate cancer. It has been found to be associated both in preclinical models and in patients with poor response to abiraterone and enzalutamide—AR pathway inhibitors,” Berchuck says.

“I think this raises some interesting questions about [if we] can we leverage that to sort of think about improving outcomes for this seemingly poor-risk patient group?” he adds.

REFERENCE:

Berchuck JE, Ravi P, D’Ippolito, et al. Plasma epigenomic profiling to reveal molecular correlates of response and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43:5074. doi:​​10.1200/JCO.2025.43.16_suppl.5074