title: PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.
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.
authors: 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.
authors: Yanjie
authors: Y
authors: Zhang
authors: Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors: Xiaowen
authors: X
authors: Wang
authors: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors: Xiaoyu
authors: X
authors: Qin
authors: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors: Xinxin
authors: X
authors: Wang
authors: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors: Feng
authors: F
authors: Liu
authors: 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.
authors: Eileen
authors: E
authors: White
authors: 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.
authors: X F Steven
authors: XF
authors: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: Cancer; PDX; Signal transduction; Targeted therapy; mTOR; p38