期刊
MOLECULAR CANCER THERAPEUTICS
卷 20, 期 7, 页码 1246-1256出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-19-1043
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资金
- NIH [R01 CA161976, T32 CA211034]
- Pancreatic Cancer Action Network Translational Research Grant [15-65-25-MERC]
- Sylvester Comprehensive Cancer Center
- NIH NCI [R03 CA249401]
- NCI of the NIH [P30CA240139]
The expression of p16 is significantly reduced in PDAC tumors, while combination of MEKi and CDK4/6i can significantly decrease cell proliferation in PDAC cells. By promoting senescence-mediated growth arrest, MEKi with CDK4/6i reduces tumor cell proliferation and attenuates tumor growth in PDAC models.
Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDK) that induce cell-cycle progression. p16(INK4a) (p16), encoded by the gene CDKN2A, is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mutations in and subsequent loss of the p16 gene occur in PDAC at a rate higher than that reported in any other tumor type and results in Rb inactivation and unrestricted cellular growth. Therefore, strategies targeting downstream RAS pathway effectors combined with CDK4/6 inhibition (CDK4/6i) may have the potential to improve outcomes in this disease. Herein, we show that expression of p16 is markedly reduced in PDAC tumors compared with normal pancreatic or pre-neoplastic tissues. Combined MEK inhibition (MEKi) and CDK4/6i results in sustained downregulation of both ERK and Rb phosphorylation and a significant reduction in cell proliferation compared with monotherapy in human PDAC cells. MEKi with CDK4/6i reduces tumor cell proliferation by promoting senescence-mediated growth arrest, independent of apoptosis in vitro. We show that combined MEKi and CDK4/6i treatment attenuates tumor growth in xenograft models of PDAC and improves overall survival over 200% compared with treatment with vehicle or individual agents alone in Ptf1acre/thorn;LSL-KRAS(G12D/+);Tgfbr2(flox/flox) (PKT) mice. Histologic analysis of PKT tumor lysates reveal a significant decrease in markers of cell proliferation and an increase in senescence-associated markers without any significant change in apoptosis. These results demonstrate that combined targeting of both MEK and CDK4/6 represents a novel therapeutic strategy to synergistically reduce tumor growth through induction of cellular senescence in PDAC.
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