In the present study, bortezomib treatment resulted in pro-apoptotic and anti-proliferative effects in KIT independent GIST cell lines through inhibition of cyclin D1 and Hippo/YAP signaling which may be a promising strategy for the future treatment of imatinib-resistant GISTs, and specifically for the as of now untreatable KIT-independent tumors. Here, CCND1 is linked to gastrointestinal stromal tumor.