Gene editing restores treatment sensitivity in melanoma

In a potential advance for melanoma patients, researchers at ChristianaCare’s Gene Editing Institute have used CRISPR gene editing tools to disable a gene mutation often seen in aggressive forms of this dangerous skin cancer that renders promising treatments ineffective.

The study, published in the October 10 issue of the CRISPR Journal, focused on melanoma cells taken from a patient whose cancer had developed a mutation that causes drugs that can slow the progress of the disease to stop working.

The scientists used CRISPR gene editing tools to disable the mutation and restore treatment sensitivity to the cancer cells in a way that appears to minimize risks of dangerous side effects. This approach is tumor-specific and will target melanoma tumor cells and leave healthy cells alone, restoring sensitivity to anticancer drugs only in the tumor cells.

‘A major step forward’ for melanoma treatment

“This study validates our previous research findings in lung cancer that CRISPR gene editing can disable genes involved in resistance to cancer treatments, and this now appears to extend to patients with melanoma,” said Eric Kmiec, Ph.D., executive director and chief scientific officer of ChristianaCare’s Gene Editing Institute, and senior author of the study.

This treatment could be delivered intravenously or by direct injection and represents a major step forward. This trend we are finding is extremely hopeful for people with cancer that is often resistant to current treatments like chemotherapy.”

Eric Kmiec, Executive Director and Chief Scientific Officer, ChristianaCare’s Gene Editing Institute

The experiment with drug-resistant melanoma cells was inspired by the Gene Editing Institute’s success in using CRISPR to disable a gene that produces a protein linked to drug resistance in lung cancer.

In both cases, the goal is to direct CRISPR to target genetic mutations that interfere with cancer treatment while mindful of a potential CRISPR risk: that an edit targeting a health problem can also disrupt gene functions that provide health benefits.

“We’re trying to advance CRISPR’s potential to safely address a major challenge that occurs with melanoma and a number of other cancers, which is the emergence of genetic mutations that help them develop resistance to proven treatments,” said Brett Sansbury, Ph.D., the principal author of the study.

Using CRISPR to address a dim prognosis for advanced melanoma 
For the current study, researchers at the Gene Editing Institute focused on patients whose melanoma, which typically begins as skin lesions, has spread or “metastasized” to other parts of the body and is no longer treatable with surgery. About half of these patients have a type of melanoma that is initially responsive to a widely used drug regimen. However, within a year, most of them develop resistance and face a poor prognosis.

The researchers focused on a mutation within the NRAS gene. In the human body, healthy NRAS genes control important, basic biological processes, like cell division. But mutated forms are implicated in driving a variety of cancers. Many patients with advanced melanoma eventually develop a type of NRAS mutation that causes treatments that had been keeping their cancer in check to stop working. Even worse, the study notes that there is evidence that the mutation can cause continued treatment to accelerate the cancer’s spread.

Kmiec said the challenge for his team — and for any team exploring CRISPR-related patient treatments — was to avoid a gene edit that causes “collateral damage.” He said that without proper guidance, a CRISPR edit may not be able to distinguish between a healthy and dangerously mutated form of the NRAS gene. It could end up altering both, he said, which could lead to significant risks for patients.

The Gene Editing Institute team addressed this dilemma by focusing on a short sequence of DNA code that is unique to the harmful NRAS mutation seen in melanoma patients. They used the code as something of a homing beacon for implementing precision-guided CRISPR gene edits that ignored healthy NRAS genes and targeted only the NRAS gene linked to treatment-resistant melanoma.