Should we keep rocking? Portraits from targeting Rho kinases in cancer

Abstract

Cancer targeted therapy, either alone or in combination with conventional chemotherapy, could allow the survival of patients with neoplasms currently considered incurable. In recent years, the dysregulation of the Rho-associated coiled-coil kinases (ROCK1 and ROCK2) has been associated with increased metastasis and poorer patient survival in several tumor types, and due to their essential roles in regulating the cytoskeleton, have gained popularity and progressively been researched as targets for the development of novel anti-cancer drugs. Nevertheless, in a pediatric scenario, the influence of both isoforms on prognosis remains a controversial issue. In this review, we summarize the functions of ROCKs, compile their roles in human cancer and their value as prognostic factors in both, adult and pediatric cancer. Moreover, we provide the up-to-date advances on their pharmacological inhibition in pre-clinical models and clinical trials. Alternatively, we highlight and discuss detrimental effects of ROCK inhibition provoked not only by the action on off-targets, but most importantly, by pro-survival effects on cancer stem cells, dormant cells, and circulating tumor cells, along with cell-context or microenvironment-dependent contradictory responses. Together these drawbacks represent a risk for cancer cell dissemination and metastasis after anti-ROCK intervention, a caveat that should concern scientists and clinicians.

Keywords: AR-12286 (Pubchem CID: 66906051); AT13148 (Pubchem CID: 24905401); Ewing’s sarcoma; Fasudil (Pubchem CID: 3547); H-1152 (Pubchem CID: 448043); LX7101 (Pubchem CID: 56962369); Osteosarcoma; Pediatric tumor; RKI-1447 (Pubchem CID: 60138149); ROCK; Ripasudil (Pubchem CID: 9863672); Wilm’s tumor; Y-27632; Y-27632 (Pubchem CID: 448042); Y-33075 (Pubchem CID: 9810884); YM529 (Pubchem CID: 130956).