Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer
Menée à l'aide de lignées cellulaires, de sphéroïdes et de xénogreffes de cancer humain de la prostate sur des modèles murins, cette étude met en évidence l'intérêt de cibler la phosphoinositide kinase PIKfyve pour inhiber l'autophagie des cellules cancéreuses et augmenter l'efficacité antitumorale des inhibiteurs de point de contrôle immunitaire
Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I–cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The antitumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon-γ pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve knockdown recapitulated ESK981’s antitumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in patients with advanced prostate cancer and be an effective treatment strategy alone or in combination with immunotherapies.