Kill, but not all
Melanoma is known to be different in different patients, but genetic variability is also common among cells within the same tumor. In a new study conducted at the Moffitt Cancer Center, it was found that differences at the level of individual cells will help predict the response to therapy with a BRAF proto-oncogene inhibitor, and using these differences can improve patient outcomes.
Approximately half of all melanoma patients have mutations in the BRAF gene that contribute to the growth of cancer. Drugs targeting BRAF and the downstream signaling protein MEK have significantly improved treatment outcomes, but with progressive melanoma it is rarely possible to achieve recovery with these drugs: most patients develop drug resistance over time and relapse occurs. At the same time, some patients with BRAF-mutated melanoma can be successfully treated with BRAF or MEK inhibitors. The researchers decided to determine which differences between cells in the same tumor lead to a different response to BRAF/MEK inhibitors.
The research team assessed the variability of melanoma cells and their response to treatment with a BRAF inhibitor by analyzing RNA expression patterns in individual cells from melanoma cell lines and tumor samples taken from patients. They found that melanoma cells can be in four different states with different patterns of gene expression.
Condition 1: Cells divide more frequently and are more sensitive to BRAF inhibitors.
State 2: Cells divide less actively, higher level of MAPK signaling.
State 3: Cells with high expression of EGFR, c-JUN and Axl genes are more resistant to BRAF inhibitors.
State 4: cells amenable to the mechanism of cell death.
The researchers found that maintaining a population of cells in a drug-sensitive "State 1" is crucial for effective treatment. Cell lines that lacked a population of cells in "State 1" were more resistant to BRAF inhibitor therapy.
These observations, as well as evolutionary principles, were used to create a mathematical model to show that it is possible to maintain drug-sensitive cell populations in "State 1" using an adaptive dosing schedule.
As a rule, patients with melanoma are treated according to a continuous dosing scheme in order to kill many cancer cells as quickly as possible. This approach to dosing often leads to the development of populations of drug-resistant tumor cells. During the adaptive dosing regimen, the decision to carry out or start drug treatment is based on the predicted tumor growth and individual factors.
If an initial reduction of the tumor is achieved and the malignant cells sensitive to treatment are preserved, an uncontrolled increase in the number of more stable cellular conditions can be prevented.
The researchers confirmed the created mathematical model in experiments on mice, showing that adaptive dosing schemes lead to stronger antitumor reactions compared to standard continuous dosing schemes. They hope that studies of cell lines and mouse models will lead to improved approaches to the treatment of patients.
The results also support the concept that resistance can be delayed by adaptive planning of existing approved drugs with benefits in the form of reduced drug exposure and reduced toxicity to the patient.
Article I. Smalley et al. Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma is published in the journal EBioMedicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert: Melanoma variability at the single-cell level predicts treatment responses.