Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors
dc.citation.epage | 559 | en_US |
dc.citation.issueNumber | 5 | en_US |
dc.citation.spage | 542 | en_US |
dc.citation.volumeNumber | 24 | en_US |
dc.contributor.author | Sahin, O. | en_US |
dc.contributor.author | Wang, Q. | en_US |
dc.contributor.author | Brady, S. W. | en_US |
dc.contributor.author | Ellis, K. | en_US |
dc.contributor.author | Wang, H. | en_US |
dc.contributor.author | Chang, C. C. | en_US |
dc.contributor.author | Zhang, Q. | en_US |
dc.contributor.author | Priya, P. | en_US |
dc.contributor.author | Zhu, R. | en_US |
dc.contributor.author | Wong, S. T. | en_US |
dc.contributor.author | Landis, M. D. | en_US |
dc.contributor.author | Muller, W. J. | en_US |
dc.contributor.author | Esteva, F. J. | en_US |
dc.contributor.author | Chang, J. | en_US |
dc.contributor.author | Yu, D. | en_US |
dc.date.accessioned | 2015-07-28T12:02:12Z | |
dc.date.available | 2015-07-28T12:02:12Z | |
dc.date.issued | 2014 | en_US |
dc.department | Department of Molecular Biology and Genetics | en_US |
dc.description.abstract | 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 various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib 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 manifesting 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 demonstrated 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 guided 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. | en_US |
dc.description.provenance | Made available in DSpace on 2015-07-28T12:02:12Z (GMT). No. of bitstreams: 1 8143.pdf: 1866094 bytes, checksum: bb02402f42169f4c74fb7ce6fd2ba480 (MD5) | en |
dc.identifier.doi | 10.1038/cr.2014.37 | en_US |
dc.identifier.issn | 1001-0602 | |
dc.identifier.uri | http://hdl.handle.net/11693/12616 | |
dc.language.iso | English | en_US |
dc.publisher | Nature Publising Group | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1038/cr.2014.37 | en_US |
dc.source.title | Cell Research | en_US |
dc.subject | Bez235 | en_US |
dc.subject | Erbb2 Stabilization | en_US |
dc.subject | Sequential Therapy | en_US |
dc.subject | Targeted Therapy | en_US |
dc.subject | Trastuzumab Resistance | en_US |
dc.subject | Tumor Evolution | en_US |
dc.title | Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors | en_US |
dc.type | Article | en_US |
Files
Original bundle
1 - 1 of 1
Loading...
- Name:
- Biomarker_-_guided_sequential_targeted_therapies_to_overcome_therapy_resistance_in_rapidly_evolving_highly_aggressive_mammary_tumors.pdf
- Size:
- 1.78 MB
- Format:
- Adobe Portable Document Format
- Description:
- Full printable version