Release date: 2018-03-06
Cancer Discovery reports a pre-existing rare mutation and points to a potential treatment to address this thorny problem.
Researchers at the University of Texas Anderson Cancer Center found that after receiving a combination of targeted therapies, a melanoma patient showed a strong drug-resistant mutation in the tumor. From the beginning, the mutation has been lurking in the tumor to hinder treatment. .
Dr. Lawrence Kwong, Assistant Professor of Translational Molecular Pathology, is the leader of the study, and his team is dedicated to finding a mechanism by which NRAS-mutant melanoma develops resistance to MEK and CDK4 inhibitor combination therapy.
A 59-year-old NRAS mutation in stage III malignant melanoma was enrolled in a clinical trial of MEK and CDK4 inhibitor combination therapy. At the beginning of treatment, the patient's tumor burden decreased by 39%. However, in the latter stage of treatment, tumor resistance increased rapidly and cancer continued to spread.
The researchers analyzed a series of biopsies before and after treatment, and finally found the latent mutations that existed before, and then developed a potential therapy to address this thorny problem.
They performed genome-wide sequencing of resistant tumors after treatment in patients. After only 16 days of treatment, PIK3CA mutations were detected in patients (the effect is to promote tumor growth). Kwong and colleagues decided to re-examine the tissue biopsy samples before treatment, and the PIK3CA mutation was not previously detected in this area. Using the amplification method developed by Dr. David Zhang, assistant professor of bioengineering at Rice University, the team examined seven regions of the sample, three of which detected PIK3CA mutations. Prior to treatment, PIK3CA mutations were spatially dispersed and sparsely populated, making it difficult to detect successfully by single-zone sampling.
In the past, many scientists believe that the PIK3CA gene mutation is a drug resistance mutation obtained after treatment. The study by Dr. Kwong and colleagues revealed that this rare mutation turned out to be a hidden face of the tumor.
Initially rare, then rapidly expanding
"This study was the first to use high-resolution analysis to re-examine multiple areas of pre-treatment tumor biopsies. Six biopsies were used to track resistance mutations during treatment," Kwong said. "We can say that this mutation is very rare at the beginning of treatment, but as MEK/CDK4 inhibitors continue to kill large numbers of non-resistant cells, they begin to expand rapidly."
This finding confirms that a rare mutation previously hidden in a tumor will multiply in the later stages of treatment and then cause rapid drug resistance. It is indicated that other patients may have more rare mutations below the current technical detection rate.
"We found that after a drug-resistant mutation, it is usually not known whether it is an emerging mutation or an existing mutation that has not been detected in the primary tumor," Kwong said. This problem has driven us to strengthen the methodological improvements in biopsy analysis to understand this difference and guide the subsequent more effective treatment.
The PIK3CA mutation can also be detected by liquid biopsy based on circulating DNA in the blood after the patient develops drug resistance. This is also a potential target that the research team is developing.
Potential treatment plan
MEK/CDK4 combination therapy that acts directly on PIK3CA may be too toxic. Therefore, the research team analyzed more than 300 proteins to find better therapeutic targets. In this article, they point out that the S6 protein is the only possible target for three cancer-promoting pathways. They resensitized mice treated with the MEK/CDK4 combination with S6 inhibitors and found that the drug restored the contractile tendency of PIK3CA mutant melanoma.
Kwong said that an optimized human version of the S6 inhibitor has not yet appeared, but it is indeed a potential developable target.
Source: Biopass
Eye Cream,Eye Cream For Wrinkles,Dark Circles Cream,Eye Cream For Dark Circles
Guangzhou Lingxue Cosmetics Co., Ltd , https://www.gzlxgj188.com