Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib

John J. Arcaroli, Kevin S. Quackenbush, Rebecca W. Powell, Todd M. Pitts, Anna Spreafico, Marileila Varella-Garcia, Lynne Bemis, Aik-Choon Tan, Jaclyn M. Reinemann, Basel M. Touban, Arvind Dasari, S. Gail Eckhardt, Wells A. Messersmith

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K) and Src signaling pathways commonly occur in colorectal cancer. Mutations in the PIK3CA gene are associated with an increase in severity of disease and worse clinical outcomes. Elevated levels of Src have been identified in premalignant lesions and are suggested to play a central role in tumor progression. Because these pathways appear to enhance tumor growth and metastasis, molecularly targeted agents for both pathways are currently being evaluated in early-phase clinical trials. Experimental Design: We used colorectal cancer cell lines and a patient-derived explant model to investigate the efficacy of saracatinib. Mutations in the PIK3CA were evaluated to examine the association between mutations in the PIK3CA gene and sensitivity to saracatinib. Results: We have identified a subset of patients with a PIK3CA (exon 9 and 20) mutation with increased sensitivity to saracatinib. A novel 3′ untranslated region (UTR) mutation was also shown to be associated with increased sensitivity to saracatinib and have a reduced affinity for miR-520a and miR-525a. Importantly, we show that Src inhibition reduces the interaction between Src and p85, subsequently decreasing Akt-dependent signaling. Conclusion: These results indicate that a personalized approach in targeting Src in PIK3CA-mutant patients with colorectal cancers may prove effective in a subset of patients with this genetic alteration.

Original languageEnglish
Pages (from-to)2704-2714
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number9
DOIs
Publication statusPublished - 2012 May 1
Externally publishedYes

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3' Untranslated Regions
Mutation
Colorectal Neoplasms
1-Phosphatidylinositol 4-Kinase
Genes
Exons
Neoplasms
Research Design
saracatinib
Clinical Trials
Neoplasm Metastasis
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arcaroli, J. J., Quackenbush, K. S., Powell, R. W., Pitts, T. M., Spreafico, A., Varella-Garcia, M., ... Messersmith, W. A. (2012). Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib. Clinical Cancer Research, 18(9), 2704-2714. https://doi.org/10.1158/1078-0432.CCR-11-3167

Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib. / Arcaroli, John J.; Quackenbush, Kevin S.; Powell, Rebecca W.; Pitts, Todd M.; Spreafico, Anna; Varella-Garcia, Marileila; Bemis, Lynne; Tan, Aik-Choon; Reinemann, Jaclyn M.; Touban, Basel M.; Dasari, Arvind; Eckhardt, S. Gail; Messersmith, Wells A.

In: Clinical Cancer Research, Vol. 18, No. 9, 01.05.2012, p. 2704-2714.

Research output: Contribution to journalArticle

Arcaroli, JJ, Quackenbush, KS, Powell, RW, Pitts, TM, Spreafico, A, Varella-Garcia, M, Bemis, L, Tan, A-C, Reinemann, JM, Touban, BM, Dasari, A, Eckhardt, SG & Messersmith, WA 2012, 'Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib', Clinical Cancer Research, vol. 18, no. 9, pp. 2704-2714. https://doi.org/10.1158/1078-0432.CCR-11-3167
Arcaroli JJ, Quackenbush KS, Powell RW, Pitts TM, Spreafico A, Varella-Garcia M et al. Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib. Clinical Cancer Research. 2012 May 1;18(9):2704-2714. https://doi.org/10.1158/1078-0432.CCR-11-3167
Arcaroli, John J. ; Quackenbush, Kevin S. ; Powell, Rebecca W. ; Pitts, Todd M. ; Spreafico, Anna ; Varella-Garcia, Marileila ; Bemis, Lynne ; Tan, Aik-Choon ; Reinemann, Jaclyn M. ; Touban, Basel M. ; Dasari, Arvind ; Eckhardt, S. Gail ; Messersmith, Wells A. / Common PIK3CA mutants and a novel 3′ UTR mutation are associated with increased sensitivity to saracatinib. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 9. pp. 2704-2714.
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