Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial
chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other
cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment.
Anthracyclines, such as
doxorubicin, have definite activity in this disease, and
ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that
ganetespib (IC50: 31 nM) was much more potent than
17-allylamino-17-demethoxygeldanamycin (17-AAG), a
geldanamycin derivative (IC50: 16 μM).
Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and
Caspase 3-dependent cell death. MTS assay revealed that
ganetespib synergized with both
doxorubicin and
etoposide, two
topoisomerase II inhibitors commonly used in SCLC
chemotherapy. Expression of receptor-interacting
serine/threonine-protein kinase 1 (RIP1), a
protein that may function as a pro-survival scaffold
protein or a pro-death
kinase in TNFR1-activated cells, was induced by
doxorubicin and downregulated by
ganetespib. Depletion of RIP1 by either RIP1
small interfering RNA (
siRNA) or
ganetespib sensitized
doxorubicin-induced cell death, suggesting that RIP1 may promote survival in
doxorubicin-treated cells and that
ganetespib may synergize with
doxorubicin in part through the downregulation of RIP1. In comparison to
ganetespib or
doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that
ganetespib and
doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that
ganetespib and
doxorubicin combination
therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.