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Rational Targeting of Cdc42 Overcomes Drug Resistance of Multiple Myeloma
Phuong Nguyen1,2, Jayati Chakrabarti1,2, Yuan Li1,2
1Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, United States.
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.
Insights
CASIN, a Cdc42 inhibitor, effectively targets drug-resistant multiple myeloma (MM) cells. This novel therapy overcomes resistance and shows promise for treating MM patients with limited options.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance in multiple myeloma (MM) necessitates novel therapeutic strategies.
- Cell division cycle 42 (Cdc42) GTPase is implicated in cancer cell proliferation and survival.
- Understanding resistance mechanisms is crucial for developing effective MM treatments.
Purpose of the Study:
- To evaluate CASIN, a Cdc42 inhibitor, as a potential therapeutic agent against drug-resistant multiple myeloma (MM).
- To elucidate the mechanisms by which CASIN overcomes melphalan/bortezomib resistance in MM cells.
- To assess the efficacy and safety of CASIN in preclinical models and patient-derived cells.
Main Methods:
- In vitro assessment of CASIN's effect on proliferation and survival of sensitive and resistant MM cells.
- Investigation of CASIN's impact on DNA damage repair pathways, including Fanconi anemia (FA) complementation group D2 (FANCD2) ubiquitination.
- Analysis of CASIN's effects on signaling pathways such as EGFR, STAT3, and ERK.
- In vivo studies using mouse xenografts and evaluation in patient-derived MM cells.
- Assessment of CASIN's safety profile on peripheral blood mononuclear cells (PBMC) and normal B cells.
Main Results:
- CASIN demonstrated potent inhibition of proliferation and survival in melphalan/bortezomib-resistant MM cells, exceeding the efficacy of existing drugs.
- CASIN sensitized resistant cells to melphalan/bortezomib and inhibited FANCD2 mono-ubiquitination in resistant cells, enhancing DNA damage sensitivity.
- CASIN suppressed key signaling pathways (EGFR, STAT3, ERK) more effectively in resistant cells, with ERK inhibition being critical for CASIN-induced apoptosis.
- CASIN extended survival in mouse xenograft models and induced apoptosis in patient-derived resistant MM cells.
- CASIN exhibited negligible toxicity in normal human cells.
Conclusions:
- Targeting Cdc42 with CASIN represents a promising strategy to overcome drug resistance in multiple myeloma.
- CASIN shows potential as a novel therapeutic agent for patients with refractory MM.
- Further clinical investigation of CASIN is warranted for its efficacy and safety in MM treatment.
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