Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma.
Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma.
复制标题
MEK和CDK4/6途径的结合封锁可诱导衰老以改善胰腺导管腺癌的生存。
DOI：
10.1158/1535-7163.mct-19-1043
复制
发表时间：
2021-07
影响因子：
5.7
通讯作者：
Merchant NB
中科院分区：
文献类型：
--
作者：
Willobee BA;Gaidarski AA;Dosch AR;Castellanos JA;Dai X;Mehra S;Messaggio F;Srinivasan S;VanSaun MN;Nagathihalli NS;Merchant NB
激活 KRAS 突变是胰腺导管腺癌 (PDAC) 的一个决定性特征，部分通过激活诱导细胞周期进展的细胞周期蛋白依赖性激酶 (CDK) 来促进肿瘤生长。 p16INK4a (p16) 由 CDKN2A 基因编码，是 CDK4/6 的有效抑制剂，是细胞增殖的关键检查点。 PDAC 中 p16 基因的突变和随后的丢失发生率高于任何其他肿瘤类型中报道的发生率，并导致 Rb 失活和不受限制的细胞生长。因此，针对下游 RAS 通路效应子的策略与 CDK4/6 抑制相结合可能有可能改善这种疾病的结果。在此，我们发现与正常胰腺或肿瘤前组织相比，PDAC 肿瘤中 p16 的表达显着降低。与人 PDAC 细胞的单一疗法相比，联合 MEK 抑制 (MEKi) 和 CDK4/6 抑制 (CDK4/6i) 导致 ERK 和 Rb 磷酸化持续下调，并显着减少细胞增殖。 MEKi 与 CDK4/6i 通过促进衰老介导的生长停滞来减少肿瘤细胞增殖，且与体外细胞凋亡无关。我们发现，在 Ptf1acre/+;LSL-KRASG12D/+;Tgfbr2flox/flox (PKT) 小鼠中，与单独使用载体或单独药物治疗相比，MEKi 和 CDK4/6i 联合治疗可减弱 PDAC 异种移植模型中的肿瘤生长，并将总体生存率提高 200% 以上。 PKT 肿瘤裂解物的组织学分析显示，细胞增殖标记物显着减少，衰老相关标记物增加，而细胞凋亡没有任何显着变化。这些结果表明，MEK 和 CDK4/6 的联合靶向代表了一种新的治疗策略，通过诱导 PDAC 中的细胞衰老来协同减少肿瘤生长。
Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDKs) that induce cell cycle progression. p16INK4a (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 may have the potential to improve outcomes in this disease. Herein, we show that expression of p16 is markedly reduced in PDAC tumors compared to normal pancreatic or pre-neoplastic tissues. Combined MEK inhibition (MEKi) and CDK4/6 inhibition (CDK4/6i) results in sustained downregulation of both ERK and Rb phosphorylation and a significant reduction in cell proliferation compared to 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 to treatment with vehicle or individual agents alone in Ptf1acre/+;LSL-KRASG12D/+;Tgfbr2flox/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.