Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma.
In: Molecular cancer therapeutics, Jg. 20 (2021-07-01), Heft 7, S. 1246-1256
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Zugriff:
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 Ptf1a cre/+ ; 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.
(©2021 American Association for Cancer Research.)
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Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma.
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Autor/in / Beteiligte Person: | Willobee, BA ; Gaidarski, AA ; Dosch, AR ; Castellanos, JA ; Dai, X ; Mehra, S ; Messaggio, F ; Srinivasan, S ; VanSaun, MN ; Nagathihalli, NS ; Merchant, NB |
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Zeitschrift: | Molecular cancer therapeutics, Jg. 20 (2021-07-01), Heft 7, S. 1246-1256 |
Veröffentlichung: | Philadelphia, PA : American Association for Cancer Research, Inc., c2001-, 2021 |
Medientyp: | academicJournal |
ISSN: | 1538-8514 (electronic) |
DOI: | 10.1158/1535-7163.MCT-19-1043 |
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