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.