Unraveling the mysteries of drug resistance in melanoma with CRISPR-Cas9

BRAF inhibitors are effective in metastatic melanoma, but many patients develop resistance. (National Cancer Institute)

About half of melanoma patients have mutations in BRAF genes, which can be addressed with drugs like Roche’s Zelboraf. But many patients eventually grow resistant to BRAF inhibitors, for reasons that researchers have struggled to determine.

A team of researchers at Mount Sinai School of Medicine in New York used the gene editing system CRISPR-Cas9 to discover a biological signature of drug resistance in melanoma—a biomarker that may provide a target for new treatments. It’s a gene called IGFBP2, which touches off an epigenetic process leading to resistance. They published their findings in the journal Nature Communications.

The team used CRISPR to screen BRAF-mutated melanoma cells, focusing in on “chromatin modifiers,” which are enzymes that are believed to modulate responses to targeted therapies, according to the paper. They discovered a mechanism that boosts expression levels of IGFBP2, a gene that’s associated with poor prognosis in melanoma patients. It involved SIRT6, a protein that’s key in DNA repair.

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They went on to investigate whether they could inhibit this epigenetic process by combining a BRAF inhibitor with linsitinib, a drug that Astellas Pharma was once testing in a variety of tumor types. In mouse studies, they observed a reduction in the proliferation of melanoma cells, as well as an increase in apoptosis, or programmed cell death, over BRAF inhibitors alone.

RELATED: Array’s encorafenib/binimetinib beats Roche’s Zelboraf in phase 3

Combination treatments are of increasing interest in the melanoma community, as oncologists continue to search for ways to combat drug resistance in their patients. Earlier this year, Array Biopharma revived prospects for its failed melanoma drug binimetinib, a MEK inhibitor, by pairing it with a BRAF inhibitor called encorafenib. The company announced that median overall survival in patients treated with the combo was double that of patients treated with Zelboraf alone.

The field of immuno-oncology is also benefiting from trials of combo treatments with PD-1 inhibitors like Merck’s blockbuster Keytruda. In April, Checkmate Pharmaceuticals presented promising early data from a trial combining Keytruda with its drug, which is injected straight into melanoma tumors in an effort to activate innate immunity.

The Mount Sinai researchers note in their study that elevated levels of IGFBP2 can be easily detected in urine samples, which could make it even more useful as a biomarker for melanoma prognosis and treatment.

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