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

• Published in: Cell research 2014-05, Vol.24 (5), p.542-559
• Main Authors: Sahin, Ozgur, Wang, Qingfei, Brady, Samuel W, Ellis, Kenneth, Wang, Hai, Chang, Chia-Chi, Zhang, Qingling, Priya, Preety, Zhu, Rui, Wong, Stephen T, Landis, Melissa D, Muller, William J, Esteva, Francisco J, Chang, Jenny, Yu, Dihua
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/67/1059/602; 631/67/1347; 631/67/1857; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Breast - drug effects; Breast - metabolism; Breast - pathology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Drug Resistance, Neoplasm - drug effects; ErbB2; Female; Heterogeneity; Humans; Imidazoles - pharmacology; Life Sciences; Mice; Mice, Transgenic; Molecular Targeted Therapy - methods; Original; original-article; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; PTEN Phosphohydrolase - metabolism; Quinazolines - pharmacology; Quinolines - pharmacology; Receptor, ErbB-2 - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Toxicity; Trastuzumab; Tumor Cells, Cultured; Tumors; 临床应用; 乳腺肿瘤; 侵袭性; 引导; 生物标志物; 癌症治疗; 蛋白质阵列
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2014.37

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.