Cell Death and Differentiation · 14 authors, 14 centres
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This preclinical study uses cell lines and xenograft models to show that mutant KIT signaling in GISTs is initiated from the Golgi complex via BLZF1 and that sustained ATF6 activation helps cells manage ER stress. Inhibiting ATF6 suppressed tumor growth in vitro and in vivo.
This study investigates mechanisms of mutant KIT (MT-KIT) signaling in GISTs, where MT-KIT is known to localize to the Golgi complex. Using GIST cell lines and mouse xenograft models, the authors identified BLZF1 as a novel protein that tethers MT-KIT to the Golgi, enabling its signaling. They also found that sustained activation of the transcription factor ATF6, part of the unfolded protein response, helps GIST cells manage ER stress by upregulating chaperones like HSP90, which assists MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed the growth of both imatinib-sensitive and -resistant GIST cells in vitro. In vivo, ATF6 inhibitors showed potent antitumor effects, which were enhanced with ER stress-inducing drugs. In a small human tissue cohort of 42 patients, ATF6 activation was frequent (67%) and associated with poorer relapse-free survival (P = 0.033). The study suggests GISTs bypass ER quality control via the Golgi and UPR activation, proposing BLZF1 and ATF6 as potential therapeutic targets.
