Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery.
The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Cheng-Qiong
CQ
Mao
Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Meng-Hua
MH
Xiong
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Yang
Y
Liu
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Song
S
Shen
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Xiao-Jiao
XJ
Du
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Xian-Zhu
XZ
Yang
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Shuang
S
Dou
Suzhou GenePharma, Suzhou, Jiangsu, People's Republic of China.
Pei-Zhuo
PZ
Zhang
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Jun
J
Wang
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000235:genetics* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins