title: Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non-Small Cell Lung Cancers In Vitro and In Vivo.
abstract: OBJECTIVE
  To investigate the potential roles that p16 (CDKN2A) and RB activation have in sensitization to MEK inhibitor in resistant KRAS-mutant non-small cell lung cancer cells (NSCLC) in vitro and in vivo.
  
  
  METHODS
  Cell viability was measured with MTS assays. Effects of administration of radiation and combination drug treatments were evaluated by clonogenic assay, flow cytometry, and Western blots. DNA repair was assessed using immunofluorescent analysis. Finally, lung cancer xenografts were used to examine in vivo effects of drug treatment and radiation therapy.
  
  
  RESULTS
  In this study, we showed that sensitivity to MEK inhibitor correlated to the RB/p16/CDK4 pathway and knockdown of RB induced resistance in cell lines sensitive to MEK inhibitor. Also, overexpression of p16 and inhibition of CDK4 had the ability to sensitize normally resistant cell lines. Our data indicated that the MEK inhibitor (trametinib, GSK112012) cooperated with the CDK4/6 inhibitor (palbociclib, PD0332991) to strongly reduce cell viability of KRAS-mutant NSCLCs that were resistant to the MEK inhibitor in vitro and in vivo. In addition, we report for the first time that resistance of KRAS-mutant NSCLCs to MEK inhibitor is, at least partly, due to p16 mutation status, and we described a drug combination that efficiently reactivates the RB tumor suppressor pathway to trigger radiosensitizing effects, apoptosis, and cell-cycle arrest.
  
  
  CONCLUSIONS
  Our findings suggest that MEK inhibitor in combination with CDK4/6 inhibitor has significant anti-KRAS-mutant NSCLC activity and radiosensitizing effect in preclinical models, potentially providing a novel therapeutic strategy for patients with advanced KRAS-mutant NSCLCs.
authors.affiliation: Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. bo.lu@jefferson.edu ztao@tmu.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Le Blanc
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. bo.lu@jefferson.edu ztao@tmu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents; D016160:Retinoblastoma Protein; C560077:trametinib; D019859:Proto-Oncogene Proteins c-met; D051358:Cyclin-Dependent Kinase 4; D018631:ras Proteins; C500026:palbociclib