Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors  

作　　者：Ozgur Sahin Qingfei Wang Samuel W Brady Kenneth Ellis Hai Wang Chia-Chi Chang Qingling Zhang Preety Priya Rui Zhu Stephen T Wong Melissa D Landis William J Muller Francisco J Esteva Jenny Chang Dihua Yu 

机构地区：[1]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA [2]Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey 06800 [3]Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, TX 77030, USA [4]The Methodist Cancer Center, Houston, TX 77030, USA [5]Goodman Cancer Center, McGill University, Montreal, Quebec, H3A 1A3, Canada [6]Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

出　　处：《Cell Research》2014年第5期542-559,共18页细胞研究（英文版）

摘　　要：Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of vari- ous targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strik- ingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-Iow/ trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although iapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by- passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifest- ing lapatinib resistance. Trastuzumab ＋ lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor （BEZ235） with no significant toxicity. However, our p-RTK array analysis dem- onstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib ＋ BEZ235 combination. Remarkably, this sequential application of targeted therapies guid- ed by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

关 键 词：sequential therapy tumor evolution targeted therapy trastuzumab resistance BEZ235 ErbB2 stabilization 

分 类 号：Q959.837[生物学—动物学] P618.130.1[天文地球—矿床学]