Changes in DNA (inside and out of chromosomes) are driving factors for tumorigenesis and treatment resistance

Precise treatments for melanoma and other cancers improve patient survival, but tumors often stop responding to drugs.

To study mutations in a key cancer-promoting gene pathway, researchers at the Jonsson Comprehensive Cancer Center at UCLA have developed a melanoma drug resistance model that allows them to study the structure and dynamics that lead to intrachromosomal and extrachromosomal changes.

"Tumor genomes, especially the genomes of aggressive cancers, have the ability to change rapidly and unpredictably

BRAF mutations are more common in thyroid cancer and melanoma, and have been targeted by drugs such as vemurafenib and dabrafenib and other MAPK pathway inhibitors

A fragment of chromosomal DNA that is amplified, called an amplicon, can lead to overexpression of cancer-promoting genes and those that interfere with targeted therapy

Over time, these amplicons can reintegrate into different chromosomes.

Kai Song, the first author of the study and a graduate student in Graber's lab, said: "This study aims to provide detailed information about the structure, dynamics and fragility of mapk-related local amplifications associated with melanoma resistance

Researchers used kinase inhibitors targeting the MAPK signaling pathway to treat human melanoma cell lines to establish a resistance model

Studies have found that each form of DNA provides tumor cells with different "adaptive" advantages, such as responding to changing treatment conditions

Although traditionally thought that dm cells are more plastic than HSR cells, studies have found that HSR cells also have plasticity in the number of copies of amplicons

This finding was supported by the literature and clinical research reports of the research team led by Dr.

Among other important results, the research team documented that although melanoma cells may be resistant to signaling pathway inhibitor drugs, drug treatment seems to make them vulnerable to another form of treatment

"An important value of this model system is that it allows us to use these resistance-based focused magnification methods to find new weaknesses in cancer cells

Article title

Plasticity of extrachromosomal and intrachromosomal BRAF amplifications in overcoming targeted therapy dosage challenges