Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubule-destabilizing agents in human tumor xenograft models.
OBJECTIVE
The extracellular signal-regulated kinase (ERK) pathway is upregulated in human cancers and represents a target for mechanism-based approaches to cancer treatment. However, specific blockade of the ERK pathway alone induces mostly cytostatic rather than proapoptotic effects, resulting in a limited therapeutic efficacy of inhibitors that target the mitogen-activated protein kinase/ERK kinase (MEK). Given the cytoprotective role of the ERK pathway, we examined whether its blockade by the MEK inhibitor PD184352 might enhance the therapeutic efficacy of anticancer drugs in human tumor xenograft models.


METHODS
We recently showed that blockade of the ERK pathway by MEK inhibitors enhances the induction of apoptosis by microtubule-destabilizing agents, including TZT-1027 and vinorelbine, in various tumor cells with aberrant activation of the ERK pathway in vitro. We here examined the therapeutic efficacy of the combination of PD184352 with TZT-1027 or vinorelbine in nude mice harboring HT-29 or HT1080 tumor xenografts, in which the ERK pathway is activated as a result of mutations of BRAF and NRAS, respectively.


RESULTS
Coadministration of PD184352 markedly sensitized HT-29 or HT1080 tumor xenografts to TZT-1027-induced or vinorelbine-induced cytotoxicity. Low doses of TZT-1027 or vinorelbine that by themselves showed little or moderate cytotoxicity thus suppressed the growth of HT-29 xenografts almost completely and induced essentially complete regression of HT1080 xenografts when administered with PD184352. The enhanced therapeutic efficacy of the drug combinations was achieved by a relatively transient blockade of the ERK pathway.


CONCLUSIONS
Administration of both a MEK inhibitor and a microtubule-destabilizing agent represents a promising chemotherapeutic strategy with improved safety for cancer patients.
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Kazushi
K
Watanabe
Susumu
S
Tanimura
Aya
A
Uchiyama
Toshiaki
T
Sakamoto
Takumi
T
Kawabata
Kei-ichi
K
Ozaki
Michiaki
M
Kohno
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D050257:Tubulin Modulators; D014747:Vinblastine; C105791:soblidotin; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D000077235:Vinorelbine