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Novel combinations of PI3K-mTOR inhibitors with dacomitinib or chemotherapy in PTEN-deficient patient-derived tumor xenografts
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Irene Brana1, Nhu-An Pham1, Lucia Kim1,2, Shingo Sakashita1,2, Ming Li1, Christine Ng1, Yuhui Wang1, Peter Loparco1, Rafael Sierra1, Lisa Wang1, Blaise A. Clarke2, Benjamin G. Neel1, Lillian L. Siu1 and Ming-Sound Tsao1,2
1 Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
2 Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
Ming-Sound Tsao, email:
Keywords: PI3K, PTEN, xenograft, chemotherapy, dacomitinib
Received: April 12, 2017 Accepted: June 28, 2017 Published: July 08, 2017
PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K/AKT/ mTOR pathway. Activation of this pathway has been involved in resistance to chemotherapy or anti-EGFR/HER2 therapies. We evaluated the combination of PI3K-mTOR inhibitors with chemotherapy or the pan-HER inhibitor dacomitinib in PTEN-deficient patient-derived tumor xenografts (PDX).
Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC). Two dual PI3K-mTOR inhibitors were evaluated—PF-04691502 and PF-05212384—in combination with cisplatin, paclitaxel, or dacomitinib.
The addition of PI3K-mTOR inhibitors to cisplatin or paclitaxel increased the activity of chemotherapy in the TNBC and LGSOC models; whereas no added activity was observed in the LADC model. Pharmacodynamic modulation of pS6 and pAKT was observed in the group treated with PI3K-mTOR inhibitor.
Our research suggests that the addition of a PI3K-mTOR inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in certain PTEN-deficient PDXs. However, this benefit was absent in the KRAS and TP53 mutant LADC model. The role of PTEN deficiency in the antitumor activity of these combinations should be further investigated in the clinic.
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