Pan-cancer Analysis Reveals Rho Kinase Addiction As a Vulnerability of De-Differentiated Cancer Cells

Although Rho kinase (ROCK) has been studied in tumor progression, the reliance of some cancer cells on ROCK-Myosin II for survival remains poorly understood. Using systematic analysis of ROCK inhibitor sensitivity in hundreds of cancer cell lines, we find that ROCK inhibition reduces survival of highly de-differentiated, invasive cancer cells from solid tumors. Transcriptomic analysis reveals enrichment in epithelial-to-mesenchymal transition, migration, proliferation, and inflammation genes, with reduced expression of differentiation and cell-cell junction genes like E-cadherin (CDH1). Acute myeloid leukemia (AML) shows high ROCK inhibitor response among hematological malignancies. Using in vitro and in vivo approaches, we validate biomarkers of ROCK inhibitor sensitivity in breast cancer, melanoma, and AML, demonstrating their unique addiction to Rho-ROCK-myosin II signaling for survival. Our work has important pre-clinical implications while cautions against wider use of ROCK inhibitors in patient-derived organoid cultures, where they may deplete important cancer cell populations.