Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer.
Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer.
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DOI：
10.1158/1078-0432.ccr-12-3140
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发表时间：
2013-08-01
期刊：
影响因子：
--
通讯作者：
Eckhardt SG
中科院分区：
文献类型：
--
作者：
Spreafico A;Tentler JJ;Pitts TM;Tan AC;Gregory MA;Arcaroli JJ;Klauck PJ;McManus MC;Hansen RJ;Kim J;Micel LN;Selby HM;Newton TP;McPhillips KL;Gustafson DL;Degregori JV;Messersmith WA;Winn RA;Eckhardt SG
The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS mutant colorectal cancer (CRC) who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in CRC, indicating that rational combination strategies are needed. In this study, we performed unbiased GSEA and synthetic lethality screens with selumetinib, which identified the non-canonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we utilized shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in CRC cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and demonstrated synergistic antiproliferative effects in in vitro and in vivo models of CRC. Importantly, this combination not only demonstrated tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of CRC. In mechanistic studies, we observed a trend towards increased markers of apoptosis in response to the combination of MEK and WntCa++ inhibitors, which may explain the observed synergistic antitumor effects. These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for metastatic CRC patients.
