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Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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. 

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Author information

Tao Z1, Le Blanc JM2, Wang C3, Zhan T4, Zhuang H5, Wang P5, Yuan Z5, Lu B6.​

1Department 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.

2Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

3Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.

4Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania.

5Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

6Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. bo.lu@jefferson.edu ztao@tmu.edu.cn.