G3BP1/2-Targeting\nPROTAC Disrupts Stress Granules\nDependent ATF4 Migracytosis as Cancer Therapy

Stress\ngranules (SGs) are membraneless cytoplasmic compartments\nthat form in response to stress stimuli. In these compartments, most\ntranslation factors stall, except for activating transcription factor\n4 (ATF4), which is preferentially translated to ensure cell survival\nunder stressful conditions. Cancer cells encounter various stress\nconditions in the tumor microenvironment during tumorigenesis; however,\nhow they exploit the pro-survival effects of ATF4 in SGs remains unclear.\nG3BP1/2 are central nodes of the SG network, regulating SG dynamics.\nIn this study, we designed two small molecules, #129 and PROTAC (Proteolysis\nTargeting Chimera) degrader 129 (PT-129), which specifically target\nthe NTF2L domain of G3BP1/2, a crucial hub for protein and RNA interactions.\nThese compounds inhibit the formation of stress granules in stressed\ncells and disassemble pre-existing stress granules. Furthermore, pharmacological\ninhibition by PT-129 suppressed fibroblast-mediated cancer cell growth\nin vitro and reduced tumor growth in vivo. Mechanistically, SG facilitates\nthe delivery of ATF4 from fibroblasts to tumor cells via migracytosis,\na primary mediator of fibroblast-associated tumor growth. PT-129-mediated\ndisassembly of stress granules disrupts ATF4 delivery, thereby preventing\ncancer cell proliferation. These compounds, therefore, represent powerful\ntools for gaining molecular insights into SGs and hold promise for\ncancer therapeutic interventions by modulating stress granule dynamics.