Cell signaling occurs in specialized compartments termed glycolipid enriched microdomains or lipid rafts. Thus, lipid rafts compartmentalize cellular processes by serving as organizing centers for the assembly of many signaling molecules that are central to oncogenic signaling5. It is therefore not surprising that changes in lipid raft composition in cancer cells are thought to sustain cell survival and promote chemoresistance in a number of alternative ways. However, the mechanisms by which these changes occur are largely not understood, nor is the adaptation process itself being exploited as a therapeutic target. Our in-vitro studies support a relevant role of SMO in DXR-resistance as pharmacologic inhibition or genetic depletion of SMO in DXR-resistant lymphoma cells resulted in increased chemosensitivity to DXR. We hypothesize that this new SMO function is central to the formation of a raft-localized Signal Stabilization Complex with AKT as one of the primary targets.