Journal article
MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers
Molecular cancer therapeutics, Vol.18(2), pp.346-355
02/01/2019
DOI: 10.1158/1535-7163.MCT-18-0510
PMCID: PMC6363831
PMID: 30425131
Abstract
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
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
and
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 (
< 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing
and
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% (
= 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
mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.
Details
- Title: Subtitle
- MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers
- Creators
- Stephanie L Fricke - University of Wisconsin–MadisonSusan N Payne - University of Wisconsin Carbone Cancer CenterPeter F Favreau - Morgridge Institute for ResearchJeremy D Kratz - University of Wisconsin–MadisonCheri A Pasch - University of Wisconsin Carbone Cancer CenterTyler M Foley - University of Wisconsin–MadisonAlexander E Yueh - University of Wisconsin–MadisonDana R Van De Hey - University of Wisconsin–MadisonMitchell G Depke - University of Wisconsin–MadisonDemetra P Korkos - University of Wisconsin–MadisonGioia Chengcheng Sha - University of Wisconsin–MadisonRebecca A DeStefanis - University of Wisconsin–MadisonLinda Clipson - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin Carbone Cancer CenterKayla K Lemmon - University of Wisconsin Carbone Cancer CenterBenjamin M Parsons - Gundersen Health SystemParaic A Kenny - Gundersen Health SystemKristina A Matkowskyj - William S. Middleton Memorial Veterans HospitalMichael A Newton - University of Wisconsin–MadisonMelissa C Skala - University of Wisconsin–MadisonDustin A Deming - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.18(2), pp.346-355
- DOI
- 10.1158/1535-7163.MCT-18-0510
- PMID
- 30425131
- PMCID
- PMC6363831
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- R01 CA211082 / NCI NIH HHS R01 CA205101 / NCI NIH HHS R01 CA185747 / NCI NIH HHS P30 CA014520 / NCI NIH HHS
- Language
- English
- Date published
- 02/01/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984700653202771
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