Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation.
Por:
Grasso S, Tristante E, Saceda M, Carbonell P, Mayor-López L, Carballo-Santana M, Carrasco-García E, Rocamora-Reverte L, García-Morales P, Carballo F, Ferragut JA and Martínez-Lacaci I
Publicada:
1 oct 2014
Categoría:
Cancer Research
Resumen:
Selumetinib (AZD6244, ARRY-142886) is a MEK1/2 inhibitor that has gained interest as an anti-tumour agent. We have determined the degree of sensitivity/resistance to Selumetinib in a panel of colorectal cancer cell lines using cell proliferation and soft agar assays. Sensitive cell lines underwent G1 arrest, whereas Selumetinib had no effect on the cell cycle of resistant cells. Some of the resistant cell lines showed high levels of ERK1/2 phosphorylation in the absence of serum. Selumetinib inhibited phosphorylation of ERK1/2 and RSK and had no effect on AKT phosphorylation in both sensitive and resistant cells. Furthermore, mutations in KRAS, BRAF, or PIK3CA were not clearly associated with Selumetinib resistance. Surprisingly, Selumetinib was able to inhibit phosphorylation of p70 S6 kinase (p70S6K) and its downstream target ribosomal protein S6 (RPS6) in sensitive cell lines. However, p70S6K and RPS6 phosphorylation remained unaffected or even increased in resistant cells. Moreover, in some of the resistant cell lines p70S6K and RPS6 were phosphorylated in the absence of serum. Interestingly, colorectal primary cultures derived from tumours excised to patients exhibited the same behaviour than established cell lines. Pharmacological inhibition of p70S6K using the PI3K/mTOR inhibitor NVP-BEZ235, the specific mTOR inhibitor Rapamycin and the specific p70S6K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells. In addition, biological inhibition of p70S6K using siRNA rendered responsiveness to Selumetinib in resistant cell lines. Furthermore, combination of p70S6K silencing and PF-47086714 was even more effective. We can conclude that p70S6K and its downstream target RPS6 are potential biomarkers of resistance to Selumetinib in colorectal cancer.
Filiaciones:
Grasso S:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Tristante E:
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain
:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Unidad de Investigación, Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain
Carbonell P:
Centro de Bioquímica y Genética Clínica, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
Mayor-López L:
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain
Carballo-Santana M:
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain
Carrasco-García E:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Rocamora-Reverte L:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Unidad de Investigación, Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain
Carballo F:
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain
Servicio de Gastroenterología, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
Ferragut JA:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Martínez-Lacaci I:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain
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