RET and cancer: Despite these advances, an ongoing challenge in RET-targeted cancer therapy is the persistence of residual tumors in most patients, which often progresses to resistant disease over time.2 Both on-target and off-target mechanisms of resistance have been reported.5–9 The primary on-target resistance mechanism to both selpercatinib and pralsetinib involves RET solvent-front G810 to C, R, and S mutations,6,8 of which G810C is most frequently associated with tumor progression.8