Introduction
GIST, RET, SDH-deficient GIST, SDH-deficient GISTs, sarcoma
CYTOPLASMIC ACCUMULATION, GASTROINTESTINAL STROMAL TUMORS, SDH, SARCOMA, GIST
Gastrointestinal stromal tumors (GIST) lacking mutations in Although KP-wGIST constitute a heterogeneous group, they do display more chromosome stability than mutated GIST, hardly exhibiting genomic imbalances at all. A large recent series of 95 KP-wGIST cases found that succinate dehydrogenase (SDH)-competent GIST represented 12%, whereas SDH-deficient GIST was 88%. Within the latter, detectable by negative SDHB immunohistochemistry, 75% had Neo-angiogenesis activation is a recognized underlying signaling in the most frequent KP-wGIST, SDH-deficient GISTs. Loss of function of SDH owing to mutational inactivation, or promoter inactivation by methylation, leads to the cytoplasmic accumulation of succinate which downregulates prolyl hydroxylase. This enzyme has a negative regulator role as regards HIF1α since it promotes its proteasomal degradation. Increased levels of HIF1α can enter the nucleus and activate the transcription of vascular endothelial growth factors (VEGFR). In fact, VEGFR expression is higher in KP-wGIST than in Regorafenib is an oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGFR), and oncogenic kinases (KIT, RET, RAF-1, BRAF, and BRAFV600E). A phase III trial showed the superiority of regorafenib over placebo in advanced GIST patients progressing to imatinib and sunitinib, with a median progression-free survival of 4.8 months vs. 0.9 months [Regorafenib is a potent inhibitor of KIT and downstream phosphorylation (AKT, MAPK, S6). Furthermore, early interstitial Cajal cell (ICC) progenitors have a phenotype of KITA phase II trial was then designed to explore regorafenib in the first-line treatment of advanced KP-wGIST, screened by NGS, with the cooperation of Spanish, French and Italian sarcoma groups.