Probabilistic graph-based model uncovers previously unseen druggable vulnerabilities in major solid cancers

Abstract

Over half cancer patients lack safe, effective, targeted therapies despite abundant molecular profiling data. Statistically recurrent cancer drivers have provided fertile ground for drug discovery where they exist. But in rare, complex, and heterogeneous cancers, strong driver signals are elusive. Moreover, therapeutically exploitable molecular vulnerabilities extend beyond classical drivers. Here we describe a novel, integrative, generalizable graph-based, cooperativity-led Markov chain model, A3D3as MVP (Adaptive AI-Augmented Drug Discovery and Development Molecular Vulnerability Picker), to identify and prioritize key druggable molecular vulnerabilities in cancer. The algorithm exploits cooperativity of weak signals within a cancer molecular network to enhance the signal of true molecular vulnerabilities. We apply A3D3as MVP to 19 solid cancer types and demonstrate that it outperforms standard approaches for target hypothesis generation by >3-fold as benchmarked against cell line genetic perturbation and drug screening data. Importantly, we demonstrate its ability to identify non-driver druggable vulnerabilities and highlight 43 novel or emergent druggable targets for these tumors.