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

• Published in: Cancer biology & therapy 2013-07, Vol.14 (7), p.597-605
• Main Authors: Zhang, Xiang-Hua, Cheng, Ying, Shin, Jung-Young, Kim, Jeong-Oh, Oh, Ji-Eun, Kang, Jin-Hyoung
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols - pharmacology; CDK4 siRNA; CDK4/6 inhibitor; Cell Line, Tumor; combination; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 6 - metabolism; Drug Synergism; Gene Knockdown Techniques; Genes, ras; Humans; KRAS; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mutation; NSCLC; paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Research Paper; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; synergistic; Transfection; Tumor Cells, Cultured
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.24592

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.