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Progress in the therapeutic inhibition of Cdc42 signalling.

ABSTRACT: Cdc42 is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation by this potent oncogene. Overexpression of Cdc42 is observed in several cancers, where it is linked to poor prognosis. As a regulator of both cell architecture and motility, deregulation of Cdc42 is also linked to tumour metastasis. Like Ras, Cdc42 and other components of the signalling pathways it controls represent important potential targets for cancer therapeutics. In this review, we consider the progress that has been made targeting Cdc42, its regulators and effectors, including new modalities and new approaches to inhibition. Strategies under consideration include inhibition of lipid modification, modulation of Cdc42-GEF, Cdc42-GDI and Cdc42-effector interactions, and direct inhibition of downstream effectors.

SUBMITTER: Murphy NP

PROVIDER: S-EPMC8286826 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This is a clinical trial investigating the effectiveness and safety of the combination of the study drugs cetuximab and erlotinib in patients with advanced (metastatic) refractory colorectal (bowel) cancer. If bowel cancer has spread to other organs (metastatic colorectal cancer), it is usually incurable and life-expectancy without treatment is less then 6 months on average. Currently, chemotherapy has been shown to have a significant impact in advanced colorectal cancer in terms of maintenance of quality of life and extension of survival. However, ultimately tumours will develop resistance to chemotherapy. Treatment options and subsequent survival at that stage are very limited. Therefore, new therapeutic approaches are urgently needed. It is common for colorectal cancer cells to contain growth receptors, like antennae, on their surface which regulate their growth. The drugs used in this trial have been shown to be effective in targeting one of these growth receptors; the epidermal growth factor receptor (EGFR). Cetuximab is an antibody (protein produced by the immune system involved in the defense of the body against infections) against EGFR. Cetuximab has been shown to improve the survival of patients with chemotherapy refractory advanced colorectal cancer. Erlotinib is a protein that prevents activation and hence signaling by EGFR. Erlotinib improves survival in patients with advanced lung cancer. Although, each of these drugs are known to be effective at inhibiting EGFR when they are given alone, at least in some cases, it is hoped that using two drugs that target the same receptor pathway in different ways will provide a more effective treatment. 50 patients from four hospitals in Australia will participate in this trial, with approximately 25 patients being enrolled at Austin Health. All participants will receive the same treatment. Neither of the study drugs are chemotherapy, and hence it is expected that the treatment would be well tolerated. The most frequent side effect associated with EGFR inhibitors is skin rash. Other possible side effects are diarrhea and low magnesium levels.

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Progress in the therapeutic inhibition of Cdc42 signalling.

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