The tumor therapy landscape of synthetic lethality

Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the computational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality. Various methods have been proposed to identify synthetic lethality interactions, but selective treatment opportunities for various tumors have not yet been explored. Here, the authors develop the Synthetic Lethality Knowledge Graph webserver (SLKG, http://www.slkg.net) to explore the comprehensive tumor therapy landscape and uncover cancer-specific susceptibilities based on the principle of synthetic lethality.

Automated summary

Synthetic lethality is becoming an important cancer therapeutic paradigm, but comprehensive selective treatment opportunities for various tumors have not been fully explored. The Synthetic Lethality Knowledge Graph (SLKG) integrates data on different tumors, drugs, and drug targets to provide therapy options for synthetic lethality and synthetic dosage lethality, prioritizing the identification of repurposable drug candidates and combinations with supporting evidence for novel tumor therapy discovery.