Metabolic biomarkers of response to the AKT inhibitor MK-2206 in pre-clinical models of human colorectal and prostate carcinoma.

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Embargo End Date

ICR Authors

Al-Saffar, Nada
 Paravati, Roberta
 Gowan, Sharon
 Boult, Jessica
 Robinson, Simon
 Leach, Martin
 Chung, Yuen-Li

Authors

Al-Saffar, NMS
Troy, H
Wong Te Fong, A-C
Paravati, R
Jackson, LE
Gowan, S
Boult, JKR
Robinson, SP
Eccles, SA
Yap, TA
Leach, MO
Chung, Y-L

Document Type

Journal Article

Date

2018-10-30

Date Accepted

2018-08-01

Abstract

BACKGROUND: AKT is commonly overexpressed in tumours and plays an important role in the metabolic reprogramming of cancer. We have used magnetic resonance spectroscopy (MRS) to assess whether inhibition of AKT signalling would result in metabolic changes that could potentially be used as biomarkers to monitor response to AKT inhibition. METHODS: Cellular and metabolic effects of the allosteric AKT inhibitor MK-2206 were investigated in HT29 colon and PC3 prostate cancer cells and xenografts using flow cytometry, immunoblotting, immunohistology and MRS. RESULTS: In vitro treatment with MK-2206 inhibited AKT signalling and resulted in time-dependent alterations in glucose, glutamine and phospholipid metabolism. In vivo, MK-2206 resulted in inhibition of AKT signalling and tumour growth compared with vehicle-treated controls. In vivo MRS analysis of HT29 subcutaneous xenografts showed similar metabolic changes to those seen in vitro including decreases in the tCho/water ratio, tumour bioenergetic metabolites and changes in glutamine and glutathione metabolism. Similar phosphocholine changes compared to in vitro were confirmed in the clinically relevant orthotopic PC3 model. CONCLUSION: This MRS study suggests that choline metabolites detected in response to AKT inhibition are time and microenvironment-dependent, and may have potential as non-invasive biomarkers for monitoring response to AKT inhibitors in selected cancer types.

Citation

British journal of cancer, 2018, 119 (9), pp. 1118 - 1128

DOI

10.1038/s41416-018-0242-3

URI

https://repository.icr.ac.uk/handle/internal/2680

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

NATURE PUBLISHING GROUP

ISSN

0007-0920

eISSN

1532-1827

Collections

Radiotherapy and Imaging
Cancer Therapeutics
Clinical Studies

Research Team

Cancer Pharmacology & Stress Response (CPSR)
Medicine Drug Development Unit (de Bono)
Magnetic Resonance
Pre-Clinical MRI

Notes