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Mol Cancer Ther. 2019 Feb;18(2):346-355. doi: 10.1158/1535-7163.MCT-18-0510. Epub 2018 Nov 13.

MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers.

Author information

1
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
2
University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
3
Morgridge Institute for Research, Madison, Wisconsin.
4
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
5
Gundersen Health System, La Crosse, Wisconsin.
6
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
7
William S Middleton Memorial Veterans Hospital, Madison, Wisconsin.
8
Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
9
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
10
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin. ddeming@medicine.wisc.edu.

Abstract

PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (-13% and -14%, respectively) compared with an increase of >200% in control (P < 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (P = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.

PMID:
30425131
PMCID:
PMC6363831
[Available on 2020-02-01]
DOI:
10.1158/1535-7163.MCT-18-0510

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