Abstract
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.
Highlights
The phosphoinositide-3-kinase (PI3K)/Akt/ mammalian target of rapamycin pathway is commonly activated in cancer by several mechanism including activating mutations of PIK3CA or AKT1 and or loss of phosphatase and tensin homolog (PTEN) [1]
Our research suggests that the addition of a PI3K-mammalian target of rapamycin (mTOR) inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in certain PTENdeficient patient-derived tumor xenografts (PDX)
To improve the clinical activity of the PI3K inhibitors, we tested several therapeutic strategies in three different tumor types using PDX selected for deficient PTEN expression as increased sensitivity to PI3K and mTOR inhibitors has been previously described in cancer cell lines [19]
Summary
The phosphoinositide-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway is commonly activated in cancer by several mechanism including activating mutations of PIK3CA or AKT1 and or loss of phosphatase and tensin homolog (PTEN) [1]. This signaling pathway is critical in the regulation of cell growth, metabolism and survival, angiogenesis, tumor invasion, cell cycle regulation and DNA repair [2, 3]. To improve the clinical activity of the PI3K inhibitors, we tested several therapeutic strategies in three different tumor types using PDX selected for deficient PTEN expression as increased sensitivity to PI3K and mTOR inhibitors has been previously described in cancer cell lines [19]. We expect that the simultaneous evaluation of these compounds in PDX may expedite the translation of the most promising combinations into the clinical setting
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
