Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary <i>KIT</i> mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. The gene discussed is FGFR1; the disease is cancer.