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. 2013 Sep 17;109(6):1562-9.
doi: 10.1038/bjc.2013.456. Epub 2013 Aug 13.

Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI

M Beloueche-Babari  1 , Y Jamin, V Arunan, S Walker-Samuel, M Revill, P D Smith, J Halliday, J C Waterton, H Barjat, P Workman, M O Leach, S P Robinson
Affiliations

Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI

M Beloueche-Babari et al. Br J Cancer. .

Abstract

Background: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts.

Methods: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis.

Results: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls.

Conclusion: Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.

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Figures

Figure 1
Figure 1
The anti-tumour effects of selumetinib therapy in V600E BRAF WM266.4 human melanoma xenografts. (A) Tumour volume measurements on days 0 and 3 showing the increase in tumour size in the vehicle-treated group over the course of treatment, while selumetinib (twice daily at 75 mg kg−1) induced tumour stasis. (B) The effect of selumetinib or vehicle treatment on WM266.4 tumour volume changes over the course of the therapy (dosing schedule indicated by black arrows) and 7 days after treatment withdrawal. (C) Western blots from representative tumours showing reduced ERK1/2 phosphorylation in selumetinib-treated compared with vehicle-treated WM266.4 human melanoma xenografts. An induction of WM266.4 melanoma tumour differentiation following selumetinib treatment is also observed, as indicated by the increased expression of the melanocyte markers gp100 and Melan-A. *P⩽0.02.
Figure 2
Figure 2
The effects of selumetinib therapy on ADC in WM266.4 human melanoma xenografts. (A) Representative anatomical T2-weighted images and parametric ADC maps acquired before (top panel) and following treatment with the MEK1/2 inhibitor selumetinib (bottom panel) in WM266.4 tumours. (B) Frequency histograms showing the change in distribution of ADC values associated with the ADC maps shown in panel A. (C) Summary of the changes in tumour ADC in the vehicle control and selumetinib cohorts before (day 0) and post treatment (day 3). Data are mean of median values, *P=0.03. NS: P⩾0.21.
Figure 3
Figure 3
Ex vivo immunohistochemical assessment of the effect of selumetinib on WM266.4 human melanoma tumours. (A) Composite images of P-ERK1/2, CC3 and H&E staining of vehicle (left) and selumetinib-treated (right) WM266.4 tumours. The insets represent higher magnification images. Arrows indicate the necrotic (N) and viable (V) tumour regions. (B) Summary of the H&E staining analysis, demonstrating a statistically significant increase in the percentage of necrosis in the tumours treated with the MEK1/2 inhibitor selumetinib compared with the controls. *P=0.05, Bar=1 mm.
Figure 4
Figure 4
The effects of selumetinib on Colo205 human colon carcinoma growth, ERK1/2 signalling and tumour ADC. (A) Tumour volume measurements showing increased day 3/day 0 tumour size in the vehicle-treated group, while the selumetinib (p.o. twice daily at 50 mg/kg)-treated tumours show stasis. (B) Western blots from representative tumours showing reduced ERK1/2 phosphorylation in selumetinib-treated compared with vehicle-treated Colo205 human tumour xenografts. (C) Summary of the DW-MRI data, showing no change in day 3/day 0 tumour ADC in the vehicle tumours, while ADC significantly increased in the selumetinib-treated group, *P⩽0.03. NS: P>0.14.
Figure 5
Figure 5
Histological assessment of apoptosis, necrosis and ERK1/2 activation in Colo205 human colon carcinoma xenografts following selumetinib therapy. (A) Composite images of Colo205 tumour tissue sections analysed by immunohistochemistry for P-ERK1/2, the apoptotic marker CC3 and H&E. The insets represent higher magnification images. Arrows indicate the necrotic (N) and viable (V) tumour regions. (B) Quantitation of the percentage of tumour necrosis (H&E staining) and the tumour cells staining positive for CC3 as determined by immunohistochemistry analysis in control and selumetinib-treated Colo205 human colon carcinoma tumours. *P⩽0.04, Bar=1 mm.
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