Skip to content

Research at St Andrews

Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer

Research output: Contribution to journalArticle


Grant D Stewart, Fiach O'Mahony, Alexander Laird, Lel Eory, Alexander Lubbock, Alan Mackay, Jyoti Nanda, Marie O'Donnell, Peter Mullen, Alan McNeill, Antony Riddick, Daniel Berney, Axel Bex, Michael Aitchison, Ian M Overton, David James Harrison, Thomas Powles

School/Research organisations


Purpose: The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC).
Experimental design: Multiple tumor samples (n=187 samples) were taken from the primary renal tumors of mccRCC patients who were sunitinib treated (n=23, SuMR clinical trial) or untreated (n=23, SCOTRRCC study). ITH of pathological grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia and stromal related genes). ITH was analysed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene expression clustering.
Results: Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and transcript changes to key targets
of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples.
Conclusions: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.


Original languageEnglish
Pages (from-to)4212-4223
JournalClinical Cancer Research
Issue number18
Early online date26 May 2015
Publication statusPublished - Sep 2015

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

    Sarr, A., Bré, J., Um, I. H., Chan, T. H., Mullen, P., Harrison, D. J. & Reynolds, P. A., 21 May 2019, In : Scientific Reports. 9, 13 p., 7643.

    Research output: Contribution to journalArticle

  2. Overcoming intratumoural heterogeneity for reproducible molecular risk stratification: a case study in advanced kidney cancer

    Lubbock, A. L. R., Stewart, G. D., O'Mahoney, F. C., Laird, A., Mullen, P., O'Donnell, M., Powles, T., Harrison, D. J. & Overton, I. M., 26 Jun 2017, In : BMC Medicine. 15, 12 p., 118.

    Research output: Contribution to journalArticle

  3. A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

    Brown, J. L., Shovman, M., Robertson, P., Boiko, A., Goltsov, A., Mullen, P. & Harrison, D. J., May 2017, In : Oncotarget. 8, 18, p. 29657-29667 11 p.

    Research output: Contribution to journalArticle

  4. Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells

    Meehan, J., Ward, C., Turnbull, A., Bukowski-Wills, J., Finch, A., Jarman, E. J., Xintaropoulou, C., Martinez-Perez, C., Gray, M., Pearson, M., Mullen, P., Supuran, C. T., Carta, F., Harrison, D. J., Kunkler, I. H. & Langdon, S., 2017, In : Oncotarget. 8, 26, p. 42857-42875

    Research output: Contribution to journalArticle

  5. Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction

    Wilkie, R. P., Neal, A., Johnston, C. A., Voûte, N., Lancefield, C. S., Stell, M., Medda, F., Makiyi, E. F., Turner, E., Ojo, O. S., Slawin, A. M. Z., Lebl, T., Mullen, P., Harrison, D. J., Ireland, C. M. & Westwood, N. J., 14 Sep 2016, In : Chemical Communications. 52, 71, p. 10747-10750

    Research output: Contribution to journalArticle

Related by journal

  1. The effect of VEGF targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer

    Sharpe, K., Stewart, G. D., Mackay, A., Van Neste, C., Rofe, C., Berney, D. M., Kayani, I., Bex, A., Wan, E., O'Mahony, F., O'Donnell, M., Chowdhury, S., Doshi, R., Ho Yen, C., Gerlinger, M., Baker, D., Smith, N. R., Davies, B. R., Sahdev, A., Boleti, E. & 7 others, de Meyer, T., Van Criekinge, W., Beltran, L., Lu, Y-J., Harrison, D., Reynolds, A. R. & Powles, T., 15 Dec 2013, In : Clinical Cancer Research. 19, 24, p. 6294-6934 641 p.

    Research output: Contribution to journalArticle

  2. Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

    Faratian, D., Zweemer, A. J. M., Nagumo, Y., Sims, A. H., Muir, M., Dodds, M., Mullen, P., Um, I., Kay, C., Hasmann, M., Harrison, D. J. & Langdon, S. P., 1 Jul 2011, In : Clinical Cancer Research. 17, 13, p. 4451-4461 11 p.

    Research output: Contribution to journalArticle

  3. Therapeutic Potential of Replication-Selective Oncolytic Adenoviruses on Cells from Familial and Sporadic Desmoid Tumors

    Peerlinck, I., Amini-Nik, S., Phillips, R. K., Iggo, R., Lemoine, N. R., Tejpar, S. & Vassaux, G., 1 Oct 2008, In : Clinical Cancer Research. 14, p. 6187-6192 6 p.

    Research output: Contribution to journalArticle

  4. Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of INK4a/ARF.

    Bean, GR., Bryson, AD., Pilie, PD., Goldenberg, V., Baker, JC., Ibarra, C., Brander, DMU., Paisie, C., Case, NR., Gauthier, M., Reynolds, P. A., Dietz, E., Ostrander, J., Scott, V., Wilke, LG., Yee, L., Kimler, BF., Fabian, CJ., Zalles, CM., Broadwater, G. & 2 others, Tlsty, TD. & Seewaldt, VL., 15 Nov 2007, In : Clinical Cancer Research. 13, p. 6834-6841 8 p.

    Research output: Contribution to journalArticle

ID: 193148604