Single-Cell Level Variability May Help Predict Responses to BRAF Inhibitors in Melanoma

New targeted therapy options, such as BRAF and MEK inhibitors, offer advanced treatment for patients with melanoma; however, genetic variability often means that patients will have different therapeutic responses.

A new study published in EBioMedicine provides insight into single-cell level differences that may help predict responses to initial BRAF inhibitor therapy and improve patient outcomes.

Most patients with advanced melanoma will receive immune checkpoint therapy as a frontline treatment.

“While this is usually undertaken with the hope of a curative response, only 30% of patients are likely to respond,” the study authors wrote.

Treatment responses often vary among patients with BRAF-mutated melanoma who receive BRAF-MEK inhibitor combination treatment, with some developing drug resistance.

For the study, the researchers assessed the variability of melanoma cells and their responses to BRAF inhibitor treatment by analyzing RNA expression patterns in single cells from melanoma cell lines and patient samples. Through their findings, they determined that melanoma cells can have 4 different states:

• Cells that divided more frequently and were more sensitive to BRAF inhibitors.
• Cells that were less proliferative with a higher level of MAPK signaling.
• Cells enriched for expression of the genes EGFR, c-JUN, and Axl and were more resistant to BRAF inhibitors.
• Cells undergoing cell death.

According to the study, “the cell state composition was dynamically regulated in response to BRAF inhibitor therapy and drug holidays.” The researchers determined that maintaining a population of cells within the drug-sensitive first state was critical to maintaining drug sensitivity. Similarly, cell lines that lacked a population of cells within state 1 were more resistant to BRAF inhibitor treatment.

Based on these findings, the researchers developed a mathematical model that optimized therapy schedules to retain the drug-sensitive population through an adaptive dosing schedule. Drug treatment initiation was determined based on predicted tumor growth and individual factors, the study authors noted. Using this personalized dosing schedule, the researchers found therapeutic responses were improved in vivo.

“Our study provides the first evidence that transcriptional heterogeneity at the single cell level predicts for initial BRAF inhibitor sensitivity,” the researchers wrote. “We further demonstrate that manipulating transcriptional heterogeneity through personalized adaptive therapy schedules can delay the time to resistance.”

Furthermore, the data may also allow new biomarkers to be developed that will allow patients to be stratified to receive BRAF-MEK inhibitor therapy as their frontline treatment in place of immunotherapy, according to the study.

The researchers concluded that a phase 1 feasibility trial of adaptive BRAF-MEK inhibitor therapy has been initiated to test the concept in this patient population.

References

Smalley I, Kim E, Li J, et al. Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma. EBioMedicine. 2019. https://www.ebiomedicine.com/article/S2352-3964(19)30627-9/pdf

Melanoma Variability at the Single-Cell Level Predicts Treatment Responses, Say Moffitt Researchers [news release]. Moffitt Cancer Center’s website. https://moffitt.org/newsroom/press-release-archive/2019/melanoma-variability-at-the-single-cell-level-predicts-treatment-responses-say-moffitt-researchers/. Accessed October 10, 2019.