Soft tissue sarcomas are rare tumors arising from soft tissue anywhere in body with more than 100 subtypes. Among them gastrointestinal stromal tumor (GIST) is a distinct tumor type characterized by the driver oncogene c-KIT mutations and corresponding molecular-targeted agents such as imatinib, sunitinib, and regorafenib. Imatinib is the established first line therapy for metastatic or recurrent GIST and shows activity with response rate of approximately 60%. Resistance to imatinib occurs primarily or secondarily. Most of the primary resistant GIST lack c-KIT mutations and called ‘wild-type GIST’. Instead of c-KIT mutations, they occasionally possess BRAF, KRAS, NF-1, or SDH alterations. Therefore multiplex test for several mutations is useful to investigate wild-type GISTs. SCRUM-Japan is a nationwide cancer genome screening for orphan-fractionated cancer. Recently the program included GIST patients and expected to show its utility. In secondary resistant GISTs, secondary c-KIT mutations in addition to the primary mutations are seen in approximately 70% of cases and the types of secondary mutations are reported to be predictive for response to the following treatment. In such cases sequential analysis for mutation during the course of the treatment could be useful. Investigator-initiated study ‘RESET’ explores correlation between secondary mutations and regorafenib.