LCL-161

Cancer, a heterogeneous disease, presents significant challenges for drug development due to its complex etiology. Drug repurposing, particularly through network medicine approaches, offers a promising avenue for cancer treatment by analyzing how drugs influence cellular networks on a systemic scale. The advent of large-scale proteomics data provides new opportunities to elucidate regulatory mechanisms specific to cancer subtypes. Herein, we present NetSDR, a Network-based Subtype-specific Drug Repurposing framework for prioritizing repurposed drugs specific to certain cancer subtypes, guided by subtype-specific proteomic signatures and network perturbations. First, by integrating cancer subtype information into a network-based method, we developed a pipeline to recognize subtype-specific functional modules. Next, we conducted drug response analysis for each module to identify the "therapeutic module" and then used deep learning to construct weighted drug response network for the particular subtype. Finally, we employed a perturbation response scanning-based drug repurposing method, which incorporates dynamic information, to facilitate the prioritization of candidate drugs. Applying the framework to gastric cancer, we attested the significance of the extracellular matrix module in treatment strategies and discovered a promising potential drug target, LAMB2, as well as a series of possible repurposed drugs. This study demonstrates a systems biology framework for precise drug repurposing in cancer and other complex diseases.

Fragile X Mental Retardation Protein 1 (FMR1) is a translational repressor crucial for regulating genes in the central nervous system. While a lack of FMR1 expression causes Fragile X Syndrome (FXS), its overexpression is implicated in various cancers, necessitating tight regulation of FMR1 protein levels for normal cell physiology. In this study, we report that FMR1 is upregulated in gastric cancer patients. Reducing FMR1 expression decreased cell growth in gastric cancer cell lines. The Smac Mimetic LCL161 reduced both FMR1 and cellular inhibitor of apoptosis protein 2 (cIAP2) levels. Suppressing cIAP2, but not cIAP1, led to decreased FMR1, while cIAP2 overexpression increased FMR1 in gastric cancer cells. We observed that cIAP2 is also upregulated in gastric cancer patients, with FMR1 and cIAP2 levels positively correlated in both gastric and colorectal cancers. Notably, cIAP2 binds FMR1 via its CARD domain, unlike most cIAP2 targets that bind the BIR domain. Furthermore, cIAP2 ubiquitinates FMR1 through its CARD-RING domains, stabilizing the protein without proteasomal degradation. FMR1, modulated by cIAP2, promotes gastric cancer cell growth. Collectively, our findings highlight FMR1's growth-promoting role in gastric cancer and reveal a novel function of cIAP2 in stabilizing FMR1 as an E3 ligase. These results suggest targeting cIAP2 could be an effective strategy for treating gastric cancer by downregulating both cIAP2 and FMR1.