Every myeloma eventually stops responding to a proteasome inhibitor. Some after years, some after a few months. What you reach for next is half of what we actually do in clinic ?
The Anderson lab's new Blood paper (Du, Fang et al, DFCI) goes somewhere different with that problem. Instead of another 20S inhibitor — bortezomib → carfilzomib → ixazomib → marizomib, two decades of the same engine — they go upstream to the 19S regulatory particle. Specifically PSMD1, the scaffold subunit that lets 19S dock to 20S. At first sounded like yah this would make sense...
The biology is clean:
• PSMD1 overexpressed in MM
• Knockdown → K48 polyubiquitin piles up despite intact 20S catalytic activity — the 26S can't assemble
• ER stress, G0/G1 arrest, caspase 3/9 cleavage, p53-independent
• Active in carfilzomib and bortezomib samples— routes around PI resistance entirely
• Kills CD138 patient cells, spares CD138-neg cells and healthy PBMCs
The immune piece is the little surprising to me. PSMD1 depletion turns on IFN-α/γ, activates cGAS-STING, flips calreticulin to the surface (immunogenic cell death), and bumps MHC I/II. Patient CD4 /CD8 T cells activate in coculture. So you're not only killing tumor — you're potentially re-priming the BM at the same time !!
I looked back on what has happened when folks tried targeting - PSMD4 and ADRM1 and both have failed. PSMD1 sits upstream of both — knock it out and PSMD4/ADRM1 fall with it, but not vice versa. The hierarchy explains why the earlier attempts stalled.
Authors explore delivery with LNP-siRNA, same chemistry as patisiran --> in NSG xenograft shows response and synergy wtih Pom.
Interesting thought from my knowledee on LNP; their biodistribution favors liver and BM. We have seen that siRNA durability in heme has been a sticky problem.
Look forward to were it goes next. If you take down the assembly platform of the 26S instead of the catalytic core, you stop chasing 20S mutations and start with a clean resistance slate. The immune activation suggests this could layer with a bispecific rather than compete.
@BloodJournal
@JanakiramMurali @bhemato @mpianko @nihrardesai89
@GKaurMD
#Myeloma #mmsm #HemOnc @NikhilMunshiMD @DanaFarber