Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer

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Koyama, F. C. ; Lopes Ramos, C. M. ; Ledesma, F. ; Alves, V. A. F. ; Fernandes, J. M. ; Vailati, B. B. ; Sao Juliao, G. P. ; Habr-Gama, A. ; Gama-Rodrigues, J. ; Perez, R. O. ; Camargo, A. A.

• Tipo de documento: Artigo Científico
• Fonte: BRITISH JOURNAL OF SURGERY; v. 105, n. 2, p. 12-pg., 2018-01-01.

Resumo

Background: Neoadjuvant chemoradiotherapy (CRT) is one of the preferred initial treatment strategies for locally advanced rectal cancer. Responses are variable, and most patients still require surgery. The aim of this study was to identify molecular mechanisms determining poor response to CRT. Methods: Global gene expression and pathway enrichment were assessed in pretreatment biopsies from patients with non-metastatic cT2-4 NO-2 rectal cancer within 7 cm of the anal verge. Downstream Akt activation was assessed in an independent set of pretreatment biopsies and in colorectal cancer cell lines using immunohistochemistry and western blot respectively. The radiosensitizing effects of the Akt inhibitor MK2206 were assessed using clonogenic assays and xenografts in immunodeficient mice. Results: A total of 350 differentially expressed genes were identified, of which 123 were upregulated and 199 downregulated in tumours from poor responders. Mitochondrial oxidative phosphorylation (P <0.001) and phosphatidylinositol signalling pathways (P <0.050) were identified as significantly enriched pathways among the set of differentially expressed genes. Deregulation of both pathways is known to result in Akt activation, and high immunoexpression of phosphorylated Akt S473 was observed among patients with a poor histological response (tumour regression grade 0-2) to CRT (75 per cent versus 48 per cent in those with a good or complete response; P = 0.016). Akt activation was also confirmed in the radioresistant cell line SW480, and a 50 per cent improvement in sensitivity to CRT was observed in vitro and in vivo when SW480 cells were exposed to the Akt inhibitor MK2206 in combination with radiation and 5-fluorouracil. Conclusion: Akt activation is a key event in the response to CRT. Pharmacological inhibition of Akt activation may enhance the effects of CRT. (AU)

• Processo FAPESP: 14/22813-6 - Estudos sobre a implicação da via de Akt e da fosforilação oxidativa mitocondrial na resistência de tumores retais a radioquimioterapia neoadjuvante
• Beneficiário: Fernanda Christtanini Koyama
• Modalidade de apoio: Auxílio à Pesquisa - Regular