BACKGROUND: The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits. METHODS: We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided. RESULTS: Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm(3), difference = 2.1 cm(3), 95% confidence interval = 0.76 to 3.51 cm(3), P = .01) and total regression of tumors by day 36 with no later relapse. CONCLUSIONS: Results showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancer patients.
BACKGROUND: The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits. METHODS: We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided. RESULTS:Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm(3), difference = 2.1 cm(3), 95% confidence interval = 0.76 to 3.51 cm(3), P = .01) and total regression of tumors by day 36 with no later relapse. CONCLUSIONS: Results showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancerpatients.
Authors: Eiki Ichihara; David Westover; Catherine B Meador; Yingjun Yan; Joshua A Bauer; Pengcheng Lu; Fei Ye; Amanda Kulick; Elisa de Stanchina; Robert McEwen; Marc Ladanyi; Darren Cross; William Pao; Christine M Lovly Journal: Cancer Res Date: 2017-04-17 Impact factor: 12.701
Authors: Samuel Seoane; Efigenia Arias; Rita Sigueiro; Juan Sendon-Lago; Anxo Martinez-Ordoñez; Esteban Castelao; Noemí Eiró; Tomás Garcia-Caballero; Manuel Macia; Rafael Lopez-Lopez; Miguel Maestro; Francisco Vizoso; Antonio Mouriño; Roman Perez-Fernandez Journal: Oncotarget Date: 2015-06-10
Authors: Noemí Eiró; Juan Sendon-Lago; Samuel Seoane; María A Bermúdez; Maria Luz Lamelas; Tomás Garcia-Caballero; José Schneider; Roman Perez-Fernandez; Francisco J Vizoso Journal: Oncotarget Date: 2014-11-15
Authors: Evandro Fei Fang; Chris Zhi Yi Zhang; Lin Zhang; Jack Ho Wong; Yau Sang Chan; Wen Liang Pan; Xiu Li Dan; Cui Ming Yin; Chi Hin Cho; Tzi Bun Ng Journal: PLoS One Date: 2012-09-05 Impact factor: 3.240