Combination of mTOR and EGFR Kinase Inhibitors Blocks mTORC1 and mTORC2 Kinase Activity and Suppresses the Progression of Colorectal Carcinoma

Quan Wang, Feng Wei, Chunsheng Li, Guoyue Lv, Guangyi Wang, Tongjun Liu, Anita Bellail, Chunhai Hao

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT S473 ) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFR T1068 ). The parallel increase of AKT S473 and EGFR T1068 in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.

Original languageEnglish (US)
Article numbere73175
JournalPLoS ONE
Volume8
Issue number8
DOIs
StatePublished - Aug 22 2013
Externally publishedYes

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colorectal neoplasms
Epidermal Growth Factor Receptor
Colorectal Neoplasms
phosphotransferases (kinases)
Phosphotransferases
phosphorylation
Phosphorylation
tyrosine
cell death
cell growth
Western blotting
cell lines
PP242
mechanistic target of rapamycin complex 1
TOR complex 2
epidermal growth factor receptors
therapeutics
receptors
Receptor Protein-Tyrosine Kinases
Cell growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Combination of mTOR and EGFR Kinase Inhibitors Blocks mTORC1 and mTORC2 Kinase Activity and Suppresses the Progression of Colorectal Carcinoma. / Wang, Quan; Wei, Feng; Li, Chunsheng; Lv, Guoyue; Wang, Guangyi; Liu, Tongjun; Bellail, Anita; Hao, Chunhai.

In: PLoS ONE, Vol. 8, No. 8, e73175, 22.08.2013.

Research output: Contribution to journalArticle

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