ArticleFrontiers in oncology2019
Rational Targeting of Cdc42 Overcomes Drug Resistance of Multiple Myeloma.
Article in Frontiers in oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 10 citations in OpenAlex.
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
- CDC42: unlocking a novel therapeutic target for primary sclerosing cholangitis through Mendelian randomization.American journal of translational research · 2025Article
- Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells.Clinical and experimental medicine · 2023Article
- Tissue-specific biological aging predicts progression in prostate cancer and acute myeloid leukemia.Frontiers in oncology · 2023Article
- miR-185-5p Regulates Inflammation and Phagocytosis through CDC42/JNK Pathway in Macrophages.Genes · 2022Article
- Progress in the therapeutic inhibition of Cdc42 signalling.Biochemical Society transactions · 2021Review
- The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma.Cancers · 2021Review
- Activation of STAT transcription factors by the Rho-family GTPases.Biochemical Society transactions · 2020Review
- Review
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Multiple myeloma (MM) drug resistance highlights a need for alternative therapeutic strategies. In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination. Mechanistically, Cdc42 activity was higher in melphalan/bortezomib-resistant cells than that in the sensitive cells. CASIN inhibited mono-ubiquitination of Fanconi anemia (FA) complementation group D2 (FANCD2) of the FA DNA damage repair pathway in melphalan-resistant but not melphalan-sensitive cells, thereby sensitizing melphalan-resistant cells to DNA damage. CASIN suppressed epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and extracellular signal-regulated kinase (ERK) activities to a larger extent in bortezomib-resistant than in melphalan-sensitive cells. Reconstitution of ERK activity partially protected CASIN-treated bortezomib-resistant cells from death, suggesting that CASIN-induced killing is attributable to suppression of ERK. Importantly, CASIN extended the lifespan of mouse xenografts of bortezomib-resistant cells and caused apoptosis of myeloma cells from bortezomib-resistant MM patients. Finally, CASIN had negligible side effects on peripheral blood mononuclear cells (PBMC) from healthy human subjects and normal B cells. Our data provide a proof of concept demonstration that rational targeting of Cdc42 represents a promising approach to overcome MM drug resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.