If you'd like to read more about why this might matter for patients, please check out this blog article written for the NIH Intramural Research Program: irp.nih.gov/blog/post/20...

With all our work, immense gratitude goes to the patients and their families who participate in clinical trials. All the credit for this effort goes to my amazing team and collaborators who have not made taggable BlueSky accounts. The work was funded by @pcf-science.bsky.social, DOD and the NCI.

What does this mean for patients? In addition to adding a HER2 inhibitor to existing hormonal therapies in the neoadjuvant or adjuvant setting, this paves the way for identifying a window-of-opportunity for HER2 inhibition in hormone-sensitive disease setting, to reduce the chance of recurrence.

The proportion of these subpopulations are important because they will inform whether a prostate tumor can respond to RTK monotherapy (in this case, low dose neratinib).

As it turns out, nearly every prostate tumor harbors both HER2-high/AR-low and AR-high/HER2-low subpopulations of cells.

Targeted inhibition of HER2 using RTKi's like afatinib effectively increase the population of cells with higher levels of AR and PSA.

That's because AR binds to an element in the ERBB2 locus that physically interacts with responsive elements that increase with enzalutamide treatment!

Single-cell sequencing of prostate cancer cells before and after enzalutamide treatment indicates that the HER2 activity-high population is a pre-existing subset of cells that mediates resistance.

This resistance is due to an inverse relationship between AR and HER2. Prostate cancer cell lines treated with AR inhibitors increase the levels of HER2 within days, as measured by flow cytometry.

We validated this at the protein level. Biopsies from prostate tumors with higher levels of HER2 protein went on to resist intense ADT.

By profiling over 140 transcriptomes from baseline biopsies prior to neoadjuvant ADT plus enzalutamide, we identified transcriptional signatures associated with final pathologic outcome. High AR activity at baseline portends a good response. High HER2 activity at baseline portends a bad response.