Novel somatic mutations to PI3K pathway genes in metastatic melanoma

BRAF(V600) inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAF(V600) inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drug's effect. We hypothesized that somatic mutati...

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Bibliographic Details
Published in:	PloS one Vol. 7; no. 8; p. e43369
Main Authors:	Shull, Austin Y, Latham-Schwark, Alicia, Ramasamy, Poornema, Leskoske, Kristin, Oroian, Dora, Birtwistle, Marc R, Buckhaults, Phillip J
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 17-08-2012 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase 1-Phosphatidylinositol 4-Kinase - genetics Adolescent Adult Aged Alleles Amino Acid Sequence Apoptosis Base Sequence Biology Cancer Cancer genetics Cancer metastasis Cancer therapies Care and treatment Cell growth Cell survival Chemoresistance Chemotherapy Clinical trials Development and progression DNA Mutational Analysis DNA sequencing Feedback Female Gene Frequency Gene sequencing Genes Genetic aspects Genetic Predisposition to Disease - genetics Genomes Genotype Health sciences Humans Inhibitors Kinases Male MAP kinase MAP Kinase Signaling System - genetics Medical research Medicine Melanoma Melanoma - genetics Melanoma - pathology Metastases Metastasis Middle Aged Mutation Neoplasm Metastasis Pathways Patients Phosphatase Proteins Proto-Oncogene Proteins B-raf - genetics PTEN protein ras Proteins - genetics Sequence Homology, Amino Acid Sequence Homology, Nucleic Acid Signal Transduction - genetics Survival TOR protein Tumors Young Adult United States > US Georgia California
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Summary:	BRAF(V600) inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAF(V600) inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drug's effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAF(V600) mutations and contribute to chemotherapeutic resistance. We performed a somatic mutation profiling study using the 454 FLX pyrosequencing platform in order to identify candidate cancer genes within the MAPK and PI3K pathways of melanoma patients. Somatic mutations of theses candidate cancer genes were then confirmed using Sanger sequencing. As expected, BRAF(V600) mutations were seen in 51% of the melanomas, whereas NRAS mutations were seen in 19% of the melanomas. However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%). Interestingly, several novel PI3K pathway mutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAF(V600) mutations in 17% of the tumors and co-occurred with 9% of NRAS mutant tumors, implying cooperativity between these pathways in terms of melanoma progression. These novel PI3K pathway somatic mutations could provide alternative survival and proliferative pathways for metastatic melanoma cells. They therefore may be potential chemotherapeutic targets for melanoma patients who exhibit resistance to BRAF(V600) inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: PJB. Performed the experiments: AYS ALS PR KL DO. Analyzed the data: AYS MRB PJB. Wrote the paper: AYS ALS MRB PJB.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0043369