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Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer

Oncogene volume 36, pages 4975–4986 (2017)Cite this article

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Abstract

Therapeutic strategies against KRAS mutant colorectal cancers are developed using cell line models, which do not accurately represent the transcriptome driven by oncogenic KRAS in tumors. We sought to identify a KRAS-associated gene signature from colorectal tumors to develop a precise treatment strategy. Integrative analysis of quantitative KRAS mutation detection and matched gene expression profiling in 55 CRC bulk tumors was carried out to define a gene signature enriched in CRC tumors with high KRAS mutation. The KRAS-associated gene signature identified exhibits functional enrichment in cell cycle and mitosis processes, and includes mitotic transcription factor, FOXM1. Combination treatment of CDK4/6 inhibitor Palbociclib and MEK inhibitor PD0325901 was tested in KRAS-mutant, BRAF-mutant CRC, normal colon epithelial lines and xenografts models to determine their efficacy and toxicity and to monitor the changes in the gene signature. Inhibiting CDK4/6, an upstream regulator of FOXM1, and MEK synergistically depleted FOXM1 and KRAS-associated gene signature, suggesting that CDK4/6 and MEK regulate the KRAS gene signature. The combined inhibition of CDK4/6 and MEK elicited a robust therapeutic response in KRAS-dependent and BRAF-mutant CRC, both in vitro and in vivo and this correlated with downregulation of the KRAS-associated gene signature. Our preclinical study demonstrated the efficacy of Palbociclib and PD0325901 combinatorial treatment selectively in KRAS-dependent and BRAF-mutant CRC but not in normal colon epithelial cells. The KRAS-associated gene signature could facilitate the identification of responsive metastatic CRC to this therapeutic strategy in clinical settings.

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Acknowledgements

This work was supported by the A*STAR of Singapore, International S&T Cooperation Program of China (ISTCP) (No. 2013DFG32990) and National High Technology Research and Development Program (863) of China (No. 2012AA02A520). We thank Puay Leng Lee for technical assistance in western blot analysis.

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Authors and Affiliations

  1. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore

    M Pek, S M J M Yatim, Y Chen, M Gong, X Jiang & Q Yu

  2. Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore

    M Pek

  3. Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Y Chen & X Wu

  4. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Y Chen & X Wu

  5. Computational Biology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore

    J Li

  6. School of Computer Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore

    F Zhang & J Zheng

  7. Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China

    X Wu

  8. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Q Yu

  9. Cancer Research Institute, Jinan University, Guangzhou, Guangdong, China

    Q Yu

  10. Cancer and Stem Cell Biology, Duke-National University of Singapore, Graduate Medical School Singapore, Singapore

    Q Yu

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Pek, M., Yatim, S., Chen, Y. et al. Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer. Oncogene 36, 4975–4986 (2017). https://doi.org/10.1038/onc.2017.120

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