Faculty Collaboration Database

MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers. Mol Cancer Ther 2019 Feb;18(2):346-355

Date

11/15/2018

Pubmed ID

30425131

Pubmed Central ID

PMC6363831

DOI

10.1158/1535-7163.MCT-18-0510

Scopus ID

2-s2.0-85061027023 (requires institutional sign-in at Scopus site)   24 Citations

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.

Author List

Fricke SL, Payne SN, Favreau PF, Kratz JD, Pasch CA, Foley TM, Yueh AE, Van De Hey DR, Depke MG, Korkos DP, Sha GC, DeStefanis RA, Clipson L, Burkard ME, Lemmon KK, Parsons BM, Kenny PA, Matkowskyj KA, Newton MA, Skala MC, Deming DA

Author

Dana Van De Hey APP Hybrid in the Neurology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenomatous Polyposis Coli Protein
Animals
Benzoxazoles
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Cohort Studies
Colorectal Neoplasms
Drug Resistance, Neoplasm
Female
Humans
Imidazoles
Male
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Mice, Transgenic
Mutation
Pyrimidines
Quinolines
Signal Transduction
Xenograft Model Antitumor Assays