(Top) Melanoma develops resistance to BRAF inhibitors, leading to cancer recurrence. (Bottom) By combining polyamine biosynthesis inhibition with BRAF inhibitors, the recurrence of cancer can be prevented, increasing the chances of complete remission.
Melanomas resistant to BRAF inhibitors show increased polyamine biosynthesis, driven by the activation of the oncogene c-Myc. This ultimately leads to increased mitochondrial activity and drug resistance. The study demonstrates that inhibiting polyamine biosynthesis can block this mechanism, overcoming drug resistance.
(Left) Synergistic cell death observed when combining BRAF inhibitors with polyamine biosynthesis inhibitors or mitochondrial activity inhibitors. (Right) Confirmation of synergistic anticancer effects when combining BRAF inhibitors and polyamine biosynthesis inhibitors.
Newswise — Melanoma is a type of cancer that originates from melanocytes, the cells responsible for producing skin pigment, and is known as the most lethal form of skin cancer due to its high rates of metastasis and recurrence. With the global trend of aging populations, the number of melanoma patients is rapidly increasing, and it is projected that by 2040, approximately 100,000 people worldwide will die from melanoma annually. In clinical practice, melanoma is currently treated with targeted therapies that inhibit the BRAF oncogene. However, drug resistance to BRAF inhibitors develops quickly, limiting the effectiveness of these treatments.
A research team led by Dr. Tackhoon Kim at the Center for Medicinal Materials Research at the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) has identified a new key mechanism behind the resistance of melanoma to BRAF inhibitors and has proposed a strategy to develop new anticancer therapies to overcome this resistance.
The research team used melanoma cell line models resistant to BRAF inhibitors and discovered that the activation of the AMD1 gene plays a crucial role in the development of drug resistance. The AMD1 gene is essential for polyamine biosynthesis, which promotes cell growth and proliferation. It was found that polyamine levels are generally higher in BRAF inhibitor resistant cancer cells. Through experiments, the team confirmed that inhibiting polyamine biosynthesis lowers resistance to BRAF inhibitors, leading to melanoma cell death.
Furthermore, the study revealed that the oncogene c-Myc triggers the increase of polyamine biosynthesis in BRAF-resistant melanoma. This increase in polyamines enhances mitochondrial protein levels, boosting mitochondrial activity and contributing to the proliferation of cancer cells resistant to treatment. The researchers identified this process as the core mechanism driving BRAF inhibitor resistance in melanoma. This is the first study in the world to pinpoint polyamine biosynthesis as a cause of BRAF inhibitor resistance. The KIST team also suggested an anticancer drug development strategy to block each stage of the resistance mechanism.
This research opens the door to developing new anticancer therapies based on regulating polyamine metabolism, which could be used to treat melanoma, a cancer that has been difficult to cure due to frequent drug resistance. The team expects to secure leading technology applicable to the BRAF inhibitor market, which is projected to reach $1 billion by 2028.
Dr. Kim of KIST stated, "We have identified the key mechanism behind drug resistance in melanoma, the deadliest form of skin cancer. We plan to verify the anticancer effects of polyamine metabolism regulation in other cancers frequently associated with BRAF mutations, such as colorectal and thyroid cancers, as part of our drug development efforts."
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KIST was established in 1966 as the first government-funded research institute in Korea. KIST now strives to solve national and social challenges and secure growth engines through leading and innovative research. For more information, please visit KIST’s website at https://eng.kist.re.kr/
This research was supported by the Ministry of Science and ICT (Minister Sang Im Yoo), through KIST’s major projects, the Mid-career Researcher Support Program, the Biomedical Technology Development Program, the Convergence Research Program, and the National Research Council of Science and Technology (NST). The findings were published in the latest issue of the international journal Molecular Cancer (IF 27.7, top 1.1% in JCR rankings).
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Credit: Korea Institute of Science and Technology
Caption: (Top) Melanoma develops resistance to BRAF inhibitors, leading to cancer recurrence. (Bottom) By combining polyamine biosynthesis inhibition with BRAF inhibitors, the recurrence of cancer can be prevented, increasing the chances of complete remission.
Credit: Korea Institute of Science and Technology
Caption: Melanomas resistant to BRAF inhibitors show increased polyamine biosynthesis, driven by the activation of the oncogene c-Myc. This ultimately leads to increased mitochondrial activity and drug resistance. The study demonstrates that inhibiting polyamine biosynthesis can block this mechanism, overcoming drug resistance.
Credit: Korea Institute of Science and Technology
Caption: (Left) Synergistic cell death observed when combining BRAF inhibitors with polyamine biosynthesis inhibitors or mitochondrial activity inhibitors. (Right) Confirmation of synergistic anticancer effects when combining BRAF inhibitors and polyamine biosynthesis inhibitors.
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