Abstract
Aberrant activation of PI3K signaling is frequently observed in lung squamous cell carcinoma (LUSC) and is strongly associated with metastasis in advanced-stage patients, but the therapeutic efficacy of PI3K inhibitors and underlying mechanisms in LUSC remain poorly defined. CYH33 is a highly selective PI3Kα inhibitor, which is in phase I/II clinical trials for the therapy of advanced solid tumors including LUSC. In this study, we investigated the efficacy of CYH33 against metastatic LUSC. We showed that CYH33 dose-dependently suppressed the motility of LUSC cells by blocking PI3K signaling and disrupting cytoskeletal structure. Oral administration of CYH33 significantly attenuated the metastasis of orthotopically implanted xenografts derived from LUSC SK-MES-1 cells. RNA-seq and GO enrichment analysis revealed that CYH33 treatment resulted in decreased infiltration of cancer-associated fibroblasts (CAFs) in primary tumors. We demonstrated that CAFs promoted the migration of SK-MES-1 cells by secreting the pro-migratory factors and activating PI3K signaling in tumor cells, which was blocked by CYH33. Moreover, CYH33 concurrently suppressed the trans-differentiation and proliferation of CAFs, thereby reducing the secretion of hepatocyte growth factor (HGF), which likely contributed to its anti-metastatic effect. Consistently, co-inoculation of SK-MES-1 cells with fibroblasts significantly potentiated tumor metastasis in nude mice, whereas CYH33 treatment robustly suppressed this process, accompanied with reduced expression of α-SMA and HGF as well as epithelial-mesenchymal transition (EMT) signature in primary tumor. Furthermore, CYH33 possessed potent activity against the growth of LUSC with hyperactivated PI3K signaling. Collectively, the dual-targeting of CYH33 that directly blocked PI3Kα in tumor cells and disrupted CAF-mediated pro-metastatic signaling supported PI3Kα inhibitors as a potential therapeutic approach for advanced LUSC.