Preclinical to clinical utility of ROCK inhibitors in cancer.

ROCK belongs to the AGC family of Ser/Thr protein kinases that are involved in many cellular processes. ROCK-driven actomyosin contractility regulates cytoskeletal dynamics underpinning cell migration, proliferation, and survival in many cancer types. ROCK1/2 play key protumorigenic roles in several subtypes and stages of cancer development. Therefore, successfully targeting ROCK and its downstream effectors presents an interesting avenue for cancer treatment. Because local use of ROCK inhibitors will reduce the side effects of systemic administration, we propose different therapeutic strategies and latest-generation ROCK inhibitors for use in the clinic.

Rho GTPase signaling in cancer progression and dissemination.

Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. Cancer is a multistep disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signaling in cancer in every step of disease progression. Rho GTPases contribute to tumor initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence, and cancer cell stemness. Rho GTPases play a major role in cell migration and in the metastatic process. They are also involved in interactions with the tumor microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.