Significance: The PROTAC SIAIS562055 sustainably degrades SOS1 and inhibits downstream ERK signaling, showing strong antiproliferative activity and synergistic effects with KRAS inhibitors in KRAS-mutant cancers and BCR–ABL inhibitors in chronic myeloid leukemia. The gene discussed is SOS1; the disease is chronic myelogenous leukemia, BCR-ABL1 positive.