Litchfield Lacey M, Boehnke Karsten, Brahmachary Manisha, Mur Cecilia, Bi Chen, Stephens Jennifer R, Sauder J Michael, Gutiérrez Sonia M, McNulty Ann M, Ye Xiang S, Wu Wenjuan, Lallena María José, Gong Xueqian, Merzoug Farhana F, Jansen Valerie M, Buchanan Sean G
Eli Lilly and Company, Indianapolis, IN, USA.
Eli Lilly and Company, New York, NY, USA.
Oncotarget. 2020 Apr 28;11(17):1478-1492. doi: 10.18632/oncotarget.27539.
Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling. The best-established mechanism of mTOR activation in cancer is via PI3K/Akt signaling, but mTOR activity can also be stimulated by CDK4 and PIM kinases. In this study, we show that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation. or mutations obviate the requirement for PIM kinase and circumvent the inhibition of S6 phosphorylation by abemaciclib. Combination with a PI3K inhibitor restored suppression of S6 phosphorylation and synergized to curtail cell growth. By combining abemaciclib with a PI3K inhibitor, three pathways (Akt, PIM, and CDK4) to mTOR activation are neutralized, suggesting a potential combination strategy for the treatment of -mutant ER+ breast cancer.
癌症中促有丝分裂信号通路的异常激活分别通过激活mTOR和S6磷酸化以及D-细胞周期蛋白激酶和Rb磷酸化来促进细胞生长和增殖。相应地，对于抑制细胞信号传导的药物而言，要实现强大的抗肿瘤功效，就需要抑制Rb和S6的磷酸化。癌症中mTOR激活最明确的机制是通过PI3K/Akt信号传导，但mTOR活性也可被CDK4和PIM激酶刺激。在本研究中，我们表明CDK4/6抑制剂阿贝西利可抑制癌细胞中的PIM激酶和S6磷酸化，同时抑制PIM、CDK4和CDK6可抑制S6和Rb磷酸化。 或 突变消除了对PIM激酶的需求，并规避了阿贝西利对S6磷酸化的抑制作用。与PI3K抑制剂联合使用可恢复对S6磷酸化的抑制，并协同抑制细胞生长。通过将阿贝西利与PI3K抑制剂联合使用，可中和激活mTOR的三条途径（Akt、PIM和CDK4），这表明了一种治疗 -突变型ER+乳腺癌的潜在联合策略。
