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Novel somatic mutations to PI3K pathway genes in metastatic melanoma
Austin Y Shull1, Alicia Latham-Schwark, Poornema Ramasamy
1Georgia Health Sciences University Cancer Center, Georgia Health Sciences University, Augusta, Georgia, United States of America.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, including novel variants, were identified in 41% of melanomas. These PI3K mutations may drive resistance to BRAF(V600) inhibitors, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRAF(V600) inhibitors offer new treatment avenues for metastatic melanoma.
- Clinical efficacy of BRAF(V600) inhibitors is limited by patient resistance.
- Somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway may contribute to this resistance.
Purpose of the Study:
- To investigate the role of PI3K pathway mutations in melanoma.
- To identify novel PI3K pathway mutations in melanoma patients.
- To explore the co-occurrence of PI3K and BRAF(V600) mutations.
Main Methods:
- Somatic mutation profiling using 454 FLX pyrosequencing.
- Identification of candidate genes in MAPK and PI3K pathways.
- Confirmation of mutations via Sanger sequencing.
Main Results:
- BRAF(V600) mutations found in 51% of melanomas; NRAS mutations in 19%.
- PI3K pathway mutations identified in 41% of melanomas, with PTEN being the most frequent (22%).
- Novel mutations discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1; PI3K mutations co-occurred with BRAF(V600) in 17% and NRAS in 9%.
Conclusions:
- Novel PI3K pathway mutations may offer alternative survival mechanisms for melanoma cells.
- These mutations can drive resistance to BRAF(V600) inhibitors.
- PI3K pathway mutations represent potential therapeutic targets for resistant melanoma.
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