Combination of pimitespib (TAS‐116) with sunitinib is an effective therapy for imatinib‐resistant gastrointestinal stromal tumors

Abstract

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second‐line therapy for GISTs. The recently‐developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS‐116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib‐resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib‐resistant GIST using imatinib‐resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib‐resistant GIST cell lines by inhibiting KIT signaling and decreasing auto‐phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia‐inducible factor‐1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib‐resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.

Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells

“…Hsp90 inhibitors have been explored as anti-cancer agents ever since they were shown to reverse the cellular transformation mediated by v-src (Whitesell et al, 1994). Roughly 20 different Hsp90 inhibitors have been, or are currently, in clinical trials (Li and Luo, 2023) and of these, only one, TAS-116/pimitespib, has gained approval for the treatment of gastrointestinal stromal tumours in Japan (Hoy, 2022;Teranishi et al, 2023a;Teranishi et al, 2023b;Doi et al, 2023). Two naturally occurring Hsp90 inhibitors, geldanamycin and radicicol, we studied for their anti-cancer properties but their use was limited by severe hepatotoxicity (Samuni et al, 2010) and propensity to be derivatized into a biologically inactive form (Agatsuma et al, 2002;Zhou et al, 2010), respectively.…”

KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST

“…It has been speculated that special regulation network exclusively in KIT-driven GIST, on the gene coding, epigenetic modification, and protein level. Available evidence that the decrease of KIT expression via HSP90- chaperone protein for the reversal of IM resistance has become a realistic possibility in clinical application [ 236 , 237 ]. This fact further improves KIT value not only as a diagnosis marker, but also could be a predictive marker for the therapeutic treatments targeting KIT expression.…”

Deciphering the tumor immune microenvironment of imatinib-resistance in advanced gastrointestinal stromal tumors at single-cell resolution

“…With longer follow-up periods, imatinib resistance has emerged as a concerning clinical problem. As a result, overcoming drug resistance has become increasingly important for clinicians in the current era of adjuvant tyrosine kinase inhibitor (TKI) therapy [ 7 – 9 ].…”