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      Epigenetic Changes of EGFR play an important role in BRAF inhibitor Resistant Cutaneous Melanomas

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          Abstract

          BRAF mutations are frequent in cutaneous melanomas and BRAF inhibitors(BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur rapidly and tumor(s) often progress thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study we developed BRAFi resistant melanoma cell lines and found that metastasis related EMT properties of BRAFi resistant cells were enhanced significantly. Upregulation of EGFR was observed in BRAFi resistant cell lines and patient tumors due to demethylation of EGFR regulatory DNA elements. EGFR induced PI3K/AKT pathway activation in BRAFi resistant cells through epigenetic regulation. Treatment of EGFR inhibitor was effective in BRAFi resistant melanoma cell lines. The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.

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          Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.

          Ramin Nazarian, Hubing Shi, Qi Wang … (2010)
          Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
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            Improving RNA-Seq expression estimates by correcting for fragment bias

            Adam Roberts, Cole Trapnell, Julie Donaghey … (2011)
            The biochemistry of RNA-Seq library preparation results in cDNA fragments that are not uniformly distributed within the transcripts they represent. This non-uniformity must be accounted for when estimating expression levels, and we show how to perform the needed corrections using a likelihood based approach. We find improvements in expression estimates as measured by correlation with independently performed qRT-PCR and show that correction of bias leads to improved replicability of results across libraries and sequencing technologies.
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              COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation

              Cory M Johannessen, Jesse Boehm, So Young Kim … (2010)
              Oncogenic mutations in the serine/threonine kinase B-RAF are found in 50–70% of malignant melanomas1. Pre-clinical studies have demonstrated that the B-RAFV600E mutation predicts a dependency on the mitogen activated protein kinase (MAPK) signaling cascade in melanoma1–5—an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials6–8. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance9–11. Identification of resistance mechanisms in a manner that elucidates alternative ‘druggable’ targets may inform effective long-term treatment strategies12. Here, we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to functionally interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (COT/TPL2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAFV600E cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in B-RAFV600E cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibition. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0426720
                Journal ID (pubmed-jr-id): 4839
                Journal ID (nlm-ta): J Invest Dermatol
                Journal ID (iso-abbrev): J. Invest. Dermatol.
                Title: The Journal of investigative dermatology
                ISSN (Print): 0022-202X
                ISSN (Electronic): 1523-1747
                Publication date Nihms-submitted: 23 January 2015
                Publication date (Electronic): 22 September 2014
                Publication date (Print): February 2015
                Publication date PMC-release: 01 August 2015
                Volume: 135
                Issue: 2
                Pages: 532-541
                Affiliations
                [1 ]Department of Molecular Oncology, John Wayne Cancer Institute(JWCI), Santa Monica, CA, 90404
                [2 ]Sequencing Center, John Wayne Cancer Institute(JWCI), Santa Monica, CA, 90404
                [3 ]Tissue Pathology and Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
                [4 ]Melanoma Institute Australia and Sydney Medical School, University of Sydney, Sydney, NSW, Australia
                [5 ]Department of Cell Research and Immunology, Tel-Aviv University, Tel-Aviv 69978, Israel
                Author notes
                Requests for reprints: Dr. Dave S.B. Hoon, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; hoon@ 123456jwci.org
                Article
                Manuscript ID: NIHMS629130
                DOI: 10.1038/jid.2014.418
                PMC ID: 4307785
                PubMed ID: 25243790
                SO-VID: 66c39657-f100-495b-a046-a5f83b62fcb8
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                Subject: Article

                ScienceOpen disciplines: Dermatology
                Keywords: melanoma,braf mutation,egfr,metastasis,braf inhibitor,epigenetics
                Data availability:
                ScienceOpen disciplines: Dermatology
                Keywords: melanoma, braf mutation, egfr, metastasis, braf inhibitor, epigenetics

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