Exploiting epigenetic modifiers to circumvent melanoma dual resistance to TCR-engineered immunotherapy- and BRAF-Kinase inhibitor
Epigenetics and Cancer, Vol: 9789400766129, Page: 203-220
2013
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
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Book Chapter Description
The discovery of activating BRAF mutation in vast majority of melanoma patients has paved the way for novel drug discovery. Targeted therapy using selective BRAF inhibitor Vemurafenib (PLX4032) and adoptive cell therapy (ACT) using MART-1 T-cell receptor (TCR)-engineered T lymphocytes (F5 CTL) both produce dramatic, but transient, clinical responses in most patients with metastatic melanoma. Adoption of bypass survival signaling pathways (e.g., AKT) and aberrant apoptotic machinery may confer resistance to death signals delivered by Vemurafenib and transgenic CTLs. We have established an in vitro model of resistant (R) lines from F5 CTL- and Vemurafenib-sensitive lines harboring BRAF under selective pressure. Interestingly, PLX-resistant tumors, while surviving high PLX4032 concentrations, develop cross-resistance to F5 CTL-killing, suggesting the use of a common apoptotic pathway by both modalities. Preliminary experiments suggest that the acquired resistance can be reversed with the histone deacetylase inhibitor (HDACi) SAHA, possibly through modulation of the expression profile of apoptotic genes. Future studies are warranted to identify the bypass signaling pathways and the molecular determinants responsible for immune- and PLX-resistance. Moreover, the exact underlying molecular mechanisms of SAHA-mediated immunosensitization need to be defined. However, these and other studies suggest that the addition of an HDACi to BRAF-based targeted therapy will immuno-sensitize PLX-resistant metastatic melanomas to F5 CTL ACT.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84932189140&origin=inward; http://dx.doi.org/10.1007/978-94-007-6612-9_11; http://link.springer.com/10.1007/978-94-007-6612-9_11; https://dx.doi.org/10.1007/978-94-007-6612-9_11; https://link.springer.com/chapter/10.1007/978-94-007-6612-9_11
Springer Science and Business Media LLC
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