title: Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.
abstract: The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.|The Centenary Institute, Newtown, NSW, Australia.|Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.affiliation: Mater Medical Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D003131:Combined Modality Therapy; D018450:Disease Progression; D016503:Drug Delivery Systems; D006801:Humans; D021621:Imaging, Three-Dimensional; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy*; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000378:metabolism* / Q000628:therapy*; D018874:Spheroids, Cellular
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
keywords: cell cycle; drug resistance; drug sensitivity; fluorescent ubiquitination-based cell cycle indicator; melanoma therapy; real-time imaging