There is increasing evidence linking oncogenic signalling of specific RTKs (e.g. MET and EGFR) with their intracellular traffic. We are focusing on HER2 trafficking in the context of HER2-amplified cancers and recently identified a supporting role for the sorting protein SORLA in HER2 recycling back to the plasma membrane. We found that disrupting SORLA-dependent recycling promotes lysosomal dysfunction and sensitises HER2-amplified cancer cells to lysosome-targeting cationic amphiphilic drugs. In our ongoing drug discovery programme, we are further delineating the mechanism of SORLA action in HER2 therapy resistance.