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

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

  • EBioMedicine. 2015 Nov 19;2(12):1944-56. doi: 10.1016/j.ebiom.2015.11.031.
Yanjie Zhang 1,  Xiaowen Wang 2,  Xiaoyu Qin 3,  Xinxin Wang 3,  Feng Liu 3,  Eileen White 4,  X F Steven Zheng 5
Affiliations

Affiliations

  • 1 Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
  • 2 Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
  • 3 Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
  • 4 Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA.
  • 5 Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, 675 Hoes Lane, Piscataway, NJ 08854, USA.
PMID: 26844273 DOI: 10.1016/j.ebiom.2015.11.031
Abstract

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.

Keywords

Cancer; PDX; Signal transduction; Targeted therapy; mTOR; p38.

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