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Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism

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Abstract

Purpose

A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer.

Methods

Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray.

Results

Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT.

Conclusions

Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.

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Acknowledgments

This work was supported in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital, and by the Taipei Veterans General Hospital, Taiwan Clinical Oncology Research Foundation, Department of Health, Taiwan (Center of Excellence for Cancer Research at Taipei Veterans General Hospital (102DHA0100184, 101DHA0100369).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan

    Guan-Da Huang, Cheng-Hwai Tzeng, Chueh-Chuan Yen & Hao-Wei Teng

  2. Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Shung-Haur Yang, Jen-Kou Lin, Wei-Shone Chen, Jeng-Kai Jiang, Yuan-Tzu Lan & Chun-Chi Lin

  3. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Cheng-Hwai Tzeng, Chueh-Chuan Yen & Hao-Wei Teng

  4. National Yang-Ming University School of Medicine, Taipei, Taiwan

    Hsei-Wei Wang, Shung-Haur Yang, Jen-Kou Lin, Wei-Shone Chen, Jeng-Kai Jiang, Yuan-Tzu Lan, Chun-Chi Lin, Wei-Lun Hwang, Cheng-Hwai Tzeng, Anna Fen-Yau Li, Chueh-Chuan Yen & Hao-Wei Teng

  5. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan

    Hsei-Wei Wang & Wei-Lun Hwang

  6. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

    Hsei-Wei Wang & Wei-Lun Hwang

  7. Department of Pathology, Taipei Veterans, General Hospital, Taipei, Taiwan

    Anna Fen-Yau Li

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Correspondence to Hao-Wei Teng.

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Wang, HW., Yang, SH., Huang, GD. et al. Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism. J Cancer Res Clin Oncol 140, 561–571 (2014). https://doi.org/10.1007/s00432-014-1596-4

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