RESUMO
Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging "Achilles heel" of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.
RESUMO
Multiple myeloma (MM) is among the most compelling examples of cancer in which research has markedly improved the length and quality of lives of those afflicted. Research efforts have led to 18 newly approved treatments over the last 12 years, including seven in 2015. However, despite significant improvement in overall survival, MM remains incurable as most patients inevitably, yet unpredictably, develop refractory disease. Recent advances in high-throughput 'omics' techniques afford us an unprecedented opportunity to (1) understand drug resistance at the genomic, transcriptomic, and proteomic level; (2) discover novel diagnostic, prognostic, and therapeutic biomarkers; (3) develop novel therapeutic targets and rational drug combinations; and (4) optimize risk-adapted strategies to circumvent drug resistance, thus bringing us closer to a cure for MM. In this review, we provide an overview of 'omics' technologies in MM biomarker and drug discovery, highlighting recent insights into MM drug resistance gleaned from the use of 'omics' techniques. Moving from the bench to bedside, we also highlight future trends in MM, with a focus on the potential use of 'omics' technologies as diagnostic, prognostic, or response/relapse monitoring tools to guide therapeutic decisions anchored upon highly individualized, targeted, durable, and rationally informed combination therapies with curative potential.
Assuntos
Biomarcadores/análise , Resistencia a Medicamentos Antineoplásicos , Genômica , Metabolômica , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Proteômica , Humanos , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Terapia de SalvaçãoRESUMO
Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway.