GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1

Lin Zheng, Wei Yang, Chong Zhang, Wan-jing Ding, Hong Zhu, Neng-ming Lin, Hong-hai Wu, Qiao-jun He, Bo Yang
Cancer Letters 2011 October 1, 309 (1): 27-36
The present study showed that GDC-0941 potently sensitized breast cancer to ABT-737 in vitro and in vivo. ABT-737 exhibited limited lethality in breast cancer cells; however, when combined with GDC-0941, it displayed strong synergistic cytotoxicity and enhanced caspase-mediated apoptosis. GDC-0941 promoted proteasomal degradation of Mcl-1, of which the overexpression has been validated to confer ABT-737 resistance, thereby enhanced the anticancer efficacy of ABT-737. Furthermore, the combination of GDC-0941 and ABT-737 exerted increased anti-tumor efficacy on MDA-MB-231 xenograft models. Overall, our data described unprecedentedly the promising therapeutic potential and underlying mechanisms of combining GDC-0941 with ABT-737 in treating breast cancer.

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