Thus, the clinical progression of GISTs after the initiation of sunitinib-based therapy is mainly due to the emergence of cross-resistant KIT-dependent GIST subclones [40,41,42] Likewise, the polyclonal heterogeneity of IM-resistant GIST subclones, including those that acquired IM resistance, due to the non-KIT-driven mechanisms might lead to the benefits observed with regorafenib used as a third-line therapy for GISTs and other TKIs used as a single-agent therapies or in combination. Here, KIT is linked to gastrointestinal stromal tumor.