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C-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

ABSTRACT: Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 ? MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

SUBMITTER: Ganguly SS

PROVIDER: S-EPMC3235241 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Ganguly S S SS Fiore L S LS Sims J T JT Friend J W JW Srinivasan D D Thacker M A MA Cibull M L ML Wang C C Novak M M Kaetzel D M DM Plattner R R

Oncogene 20110905 14

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in ...[more]

PMID: 21892207

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Project description:Although melanoma is the least frequent type of skin cancer, it accounts for the majority of skin cancer-related deaths. Large-scale sequencing efforts have led to the classification of melanoma into four major subtypes (i.e., BRAF-mutant, NRAS-mutant, NF1-deficient, and triple wild-type). These sequencing studies have also revealed that melanoma genomes are some of the most mutated genomes of all cancers and therefore have a high neoantigen load. These findings have resulted in the development and clinical use of targeted therapies against the oncogenic BRAF?MEK?ERK pathway and immune checkpoint inhibitors for the treatment of metastatic melanoma. Although some patients with metastatic melanoma benefit immensely from these transformative therapies, others either become resistant or do not respond at all. These clinical challenges have intensified the search for new drug targets and drugs that can benefit patients who are either intrinsically resistant or have acquired resistance to targeted therapies and immunotherapies. Numerous signaling pathways and oncogenic drivers can cause changes in mRNA transcription that in turn drive melanoma initiation and progression. Transcriptional regulation of mRNA expression is necessary to maintain cell identity and cellular plasticity via the regulation of transcription factor expression and function, promoter/enhancer activities, chromatin regulators, and three-dimensional genome organization. Transcriptional deregulation can arise due to genetic and/or non-genetic alterations in the genome. Specifically, these deregulated transcriptional programs can become liabilities for melanoma cells due to their acquired dependencies on these programs for survival, which can be harnessed to develop new therapies for melanoma. In this article, we present an overview of the mechanisms that result in the transcriptional deregulation of mRNA expression in melanoma cells and assess how these changes facilitate melanoma initiation and progression. We also describe how these deregulated transcriptional pathways represent new opportunities for the development of unconventional and potentially impactful treatments for metastatic melanoma.

Dataset Information

C-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Publications

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Similar Datasets

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