Kinase Inhibitor Combination Discovery
Solutions Accelerated by IsoPlexis
- Adaptive Resistance in Glioblastoma
Make decisions to predict adaptive resistance to targeted inhibitor therapeutics in oncology1
Empower discovery of combination therapies and overcoming adaptive resistance in solid tumor targeted therapies.
Uncovering the ability to predict adaptive resistance to glioblastoma and other solid tumors to targeted inhibitor therapeutics.
IsoPlexis’ single-cell phosphoproteomic analytics of a human-derived in vivo GBM model of mTORki resistance demonstrated that drug resistance can proceed via non-genetic, adaptive mechanisms that are activated within days of drugging.
The measured adaptive response points to combination therapies tested in vivo were shown to halt tumor growth. This single-cell analytic approach provided clinically actionable insights into designing combination therapies against solid tumor.
To evaluate the change in tumor heterogeneity across the three stages, we employed a functional heterogeneity index (FHI). The FHI reflects the dispersion of the functional protein levels across all single-cell assays at a specific condition. It is defined as the dissimilarity value in the agglomerative hierarchical clustering (AHC) of mean normalized single-cell data based upon Ward’s minimum variance method (Ward, 1963).
In the responsive state, there is a more than 4-fold drop in the FHI. The tumors were again probed at the resistant state (day 39 following the start of therapy). Resistance was also associated with a sharp increase in the FHI.