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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

A CDK4/6 Inhibitor Enhances Cytotoxicity of Paclitaxel in Lung Adenocarcinoma Cells Harboring Mutant KRAS as Well as Wild-Type KRAS

Xiang-Hua Zhang, Ying Cheng, Jung-Young Shin, Jeong-Oh Kim, Ji-Eun Oh, Jin-Hyoung Kang

Cancer Biol Ther. 2013 Jul;14(7):597-605.

PMID: 23792647

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP359886843-B	CINK4		359886-84-3	Price

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