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.