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A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS.

Abstract
The KRAS gain-of-function mutation confers intrinsic resistance to targeted anti-cancer drugs and cytotoxic chemotherapeutic agents, ultimately leading to treatment failure. KRAS mutation frequency in lung adenocarcinoma is ~15-30%. Novel therapeutic strategies should be developed to improve clinical outcomes in these cases. Deregulation of the p16/cyclin-dependent kinase (CDK) 4/retinoblastoma (Rb) pathway is frequently observed in various cancers and it represents an attractive therapeutic target. We compared the anti-tumor efficacy of genetically knocked-down CDK4 and a pharmacological inhibitor of CDK4/6, CINK4, in KRAS mutation-positive lung adenocarcinoma cells. We also investigated changes in anti-proliferative activity and downstream molecules with these treatments in combination with paclitaxel. CDK4 short interfering RNA (siRNA) significantly increased paclitaxel sensitivity in KRAS mutation-positive H23 cells. CINK4 demonstrated concentration- and time-dependent anti-proliferative activity in 5 adenocarcinoma lines. CINK4 induced G 1 arrest by downregulating the p16/cyclin D1/Rb pathway, resulting in apoptotic induction via increased expression of cleaved caspase3, cleaved PARP and Bax. Combined CINK4 and paclitaxel produced synergistic anti-proliferative activity and increased apoptosis through reduced cyclin D1 and Bcl-2 in KRAS mutation-positive cancer cells. These data suggest CDK4 is a promising target for development of anti-cancer drugs and CINK4 combined with paclitaxel may be an effective therapeutic strategy for enhancing anti-tumor efficacy in KRAS mutation-positive lung adenocarcinoma.
AuthorsXiang-Hua Zhang, Ying Cheng, Jung-Young Shin, Jeong-Oh Kim, Ji-Eun Oh, Jin-Hyoung Kang
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 14 Issue 7 Pg. 597-605 (Jul 2013) ISSN: 1555-8576 [Electronic] United States
PMID23792647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Paclitaxel
Topics
  • Adenocarcinoma (drug therapy, enzymology, genetics, metabolism)
  • Adenocarcinoma of Lung
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 (antagonists & inhibitors, genetics, metabolism)
  • Cyclin-Dependent Kinase 6 (antagonists & inhibitors, genetics, metabolism)
  • Drug Synergism
  • Gene Knockdown Techniques
  • Genes, ras
  • Humans
  • Lung Neoplasms (drug therapy, enzymology, genetics, metabolism)
  • Mutation
  • Paclitaxel (administration & dosage, pharmacology)
  • Protein Kinase Inhibitors (administration & dosage, pharmacology)
  • Proto-Oncogene Proteins (genetics)
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Small Interfering (administration & dosage, genetics)
  • Transfection
  • Tumor Cells, Cultured
  • ras Proteins (genetics)

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