Abstract
Whole-exome sequencing of 213 tumor samples shows that NF1 is mutated in 13.1% of melanomas. The gene is usually mutated in tumors that don't carry mutations in BRAF or NRAS, and it may be a cancer driver. However, loss of the gene didn't predict whether RAS activity increased or whether cell lines responded to inhibitors of the MAP kinase pathway, which RAS activates.
NF1 is the third most frequently mutated gene in melanoma, a new study finds, but the results suggest it's not a promising target for personalized medicine.
The two most commonly mutated genes in melanomas are BRAF and NRAS. About 50% of tumors carry an altered version of BRAF, and about 20% harbor NRAS mutations. Therapies such as vemurafenib (Zelboraf; Genentech) and dabrafenib (Tafinlar; GlaxoSmithKline) are available for patients with BRAF mutations, and researchers are trying to determine which other mutated genes could be drug targets.
Several studies, including one earlier this year from The Cancer Genome Atlas Network, found that NF1 is frequently altered in melanoma. The NF1 protein suppresses RAS family proteins, so NF1 mutations and mutations that activate RAS might cause similar effects. However, the significance of NF1 mutations for tumor development has remained unclear.
In the new study, researchers performed whole-exome sequencing on 213 melanoma samples. NF1 was mutated in 13.1% of the samples. Most NF1 mutations occurred in tumors that didn't have mutations in BRAF or NRAS. The team found that 46% of tumors with normal BRAF and NRAS had inactivating NF1 mutations.
These results suggest that NF1 is a driver for melanoma, the researchers conclude, but it alone cannot transform normal cells into malignant ones. NF1-mutant tumors carried many more mutations in other genes than did melanomas with unaltered NF1. “It means that NF1 needs a lot of help” to induce cancer, says co-author Ruth Halaban, PhD, of Yale University School of Medicine in New Haven, CT. That help often comes from mutations in other genes in the RAS pathway such as RASA2, PTPN11, and SOS1.
To determine NF1's importance for regulating RAS, Halaban and colleagues tested NRAS activity in 10 melanoma cell lines, six of which contained little or no NF1. They found that loss of NF1 didn't always unleash RAS, presumably because other inhibitors pick up the slack.
Previous studies suggested that NF1 mutations indicate tumors' sensitivity to certain drugs that suppress the MAP kinase pathway, which RAS activates. The team tested that possibility by adding either the MEK inhibitor selumetinib (AZD6244; AstraZeneca) or the ERK inhibitor SCH772984 to 21 melanoma cell lines, 10 of which carried NF1 mutations. As the researchers reported last month in Nature Genetics, the presence of NF1 mutations didn't predict tumors' sensitivity or resistance to either drug.
Overall, Halaban says, the results indicate that “NF1 cannot be used as a target, only to better understand the tumor phenotype.”
The study shows that “NF1 loss may not exactly equal RAS mutations with respect to the response to MAP kinase targeting,” says Ryan Sullivan, MD, of Harvard Medical School in Boston, MA. However, given that some of the NF1-lacking cell lines responded to MAP kinase inhibitors, he says it's worth testing these drugs in patients with NF1 mutations.
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