PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer

EBioMedicine

Xiaoyu Qin¹  Xinxin Wang¹  Feng Liu¹  Xiaowen Wang²  Yanjie Zhang²  Eileen White²  X.F. Steven Zheng² 

[1] Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China;Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA;

关键词: Targeted therapy;    Cancer;    Signal transduction;    mTOR;    p38;    PDX;   

DOI  :  10.1016/j.ebiom.2015.11.031

来源: DOAJ

【 摘 要 】

The p38 MAP kinase is a promising cancer drug target but its therapeutic effect is not fully understood. Here we report that the response of colorectal cancer (CRC) to p38 inhibitors (p38i) is highly variable: while p38i induces regression of one subgroup of CRCs, it stimulates growth of another subgroup. We further show that PP2AC is differentially expressed in the two different CRC subgroups, which determines the programing of p38-TSC-mTORC1 signaling through differential TSC2 phosphorylation at S664, 1254 and 1798, and the antitumor activity by p38i. Remarkably, modulation of PP2AC level is sufficient to reprogram p38-to-mTORC1 signaling and antitumor response. PP2AC expression accurately predicts therapeutic response to p38i in several CRC models, including a large cohort of patient-derived xenografts (PDXs). Moreover, we demonstrate that combination of p38 and mTOR kinase inhibitors effectively overcomes resistance to either inhibitor in single agent therapy. These results demonstrate that alternative routing of signal transduction underlies differential response to p38 and mTOR targeted therapies. The biomarker-guided therapeutic strategies described herein provide a compelling reason for testing in metastatic CRC patients who suffer very poor prognosis due to lack of efficacious drug therapies.

【 授权许可】

Unknown