Exploring the regulatory genome in melanoma innate resistance
Abstract/Contents
- Abstract
- Targeted therapy for cancer treatment has been confronted with acquired resistance. In metastatic melanoma, for many years conventional chemotherapy and radiation were the common treatment options. The first generation of targeted therapy against BRAFV600E, a mutation found in about 50% of metastatic melanoma, revolutionized standard treatment. This first generation targeted therapy, Vemurafenib, resulted in > 50% clinical response in the first few months of treatment. Unfortunately, drug resistance to this therapy occurs about six months to a year after treatment. Subsequently, numerous genome sequencing studies on Vemurafenib-resistant melanomas identified extensive acquired DNA mutations that up-regulate components of the MAPK signaling pathway, therefore effectively re-wiring around the initial BRAF inhibition. It is hypothesized that during targeted therapy, cancer cells initially engage an innate resistance program to survive, in order to generate secondary DNA mutations in the same pathway to be resistant to the targeted therapy (acquired resistance). Recent studies have shown that HGF in the tumor microenvironment is important for cell survival on targeted BRAF therapy. This suggest that melanoma cells must have drug response and pro-survival mechanisms, including the MET signaling pathway. Using an integrated genomics approach, we identified a dynamic genomic interaction between the MET TSS and a lineage-specific enhancer 63kb downstream during targeted BRAF inhibition. This dynamic interaction is further mediated by the melanocyte lineage master transcription factor, MITF. MITF pro-differentiation and tumorigenic function can be uncoupled by selective editing of the MET specific enhancer. This initial study showed the importance of looking at distal regulatory elements in dynamic cellular responses such as cellular reprogramming in response to drug treatment. We extended this initial study of the MET locus to look at global dynamic regulatory changes. We assessed the global open chromatin dynamics and transcriptomic changes during acute BRAF inhibition and MITF depletion. Using a statistical framework, we generated a global regulatory network of important transcriptional regulators during targeted BRAF inhibition in melanoma cells treated with vemurafenib (PLX4032). Focusing on the MITF sub-network can help identify putative MITF transcriptional co-regulators and parallel pathways during acute oncogenic signaling inhibition.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Tran-Bussat, Rose |
|---|---|
| Degree supervisor | Khavari, Paul A |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Mallick, Parag, 1976- |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Sage, Julien |
| Degree committee member | Mallick, Parag, 1976- |
| Degree committee member | Oro, Anthony, 1958- |
| Degree committee member | Sage, Julien |
| Associated with | Stanford University, Cancer Biology Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Rose Tran-Bussat. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Rose Tran
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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