It’s pleasant to sunbathe, but melanoma – the deadliest form of skin cancer that is caused by unprotected exposure to the sun – kills one person every hour. In the US alone, about 6,850 people are expected to die from the disease this year, most of them men. 

Even these days, when we all miss the open space, it is very important to protect your skin and health and maintain the smart rules of the sun – shade, hat, sunglasses, clothing, safe hours, sunscreen, drinking a lot of water and – most importantly – protecting your skin, especially during the hours of the highest radiation intensity between 10 am and 4 pm.

Melanoma often presents a rapid resistance to molecular anti-cancer therapies. Although there have been advances in targeted and immunotherapy melanoma treatments in recent years, a substantial percentage patient fails to respond or develop resistance to such therapies. 

Now, researchers at the Technion-Israel Institute of Technology in Haifa have suggested a new approach to overcoming anticancer-drug resistance in melanoma. Now, in a discovery that could in the future help address this major clinical challenge, the Israeli researchers have uncovered two proteins that play together a major role in drug resistant melanoma.

The research, just published in the Journal of Investigative Dermatology, was headed by Prof. Amir Orian (head of the lab for the study of genetic networks at the Faculty of Medicine and a member of the Technion’s Integrated Cancer Research Center of the Technion’s Rapaport Faculty of Medicine) and Dr. Emily Avitan-Hersh (a lecturer in the Technion’s Faculty of Medicine and deputy director of the dermatology department and a member of the Rambam Clinical Research Institute at Rambam Medical Center), in collaboration with Prof. Ze’ev A. Ronai of the Sanford Burnham Prebys Medical Discovery Institute in California.

In many cases, melanoma results from a mutation in an enzyme called BRAF. This mutation promotes uncontrolled cell division and prevents natural cell death, resulting in the development of cancer/melanoma tumors. Several years ago, new drugs became available that inhibit BRAF; they are currently at the forefront of treating the disease, but unfortunately, melanoma cells develop rapid resistance to the same drugs, thus reducing their effectiveness and patients’ survival rates.

A “hallmark” observation in melanoma tumors from the patients that exhibit treatment resistance are “stabilized oncoproteins.” Oncoproteins are usually short-lived cancer-causing proteins that have the ability to turn healthy cells into cancerous cells. In such melanoma tumors, they abnormally stabilize, thereby increasing their levels and pro-cancer activity. In previous experiments by Orian’s group, the oncoproteins were found to be protected against their natural protein degradation process by a protein called RNF4. 

The team noted that high RNF4 levels in melanoma tumors correlate with poor prognosis and treatment resistance. Even more notably, they found that the tumorigenic properties (tumor growth, formation, and therapy resistance) of RNF4 in melanoma demands another protein – the translation initiation factor, eIF2α. RNF4 binds to eIF2α and stabilized it, increasing p-eIF2α levels, in turn, p-eIF2α is required for RNF4 activities including the development of resistance, creating a devastating positive-feedback loop. 

The study spans the entire spectrum between basic research and clinics, from cell culture to xenografts in model mice to melanoma patients. The findings showed that increased levels of RNF4 characterize about 40% of melanoma patient tumors.

The elucidation of the RNF4 pathway in melanoma and its dependency on eIF2α has the potential to enable doctors to predict how a patients’ melanoma will response to targeted therapies, allowing doctors to better personalized treatments for individual patients. The findings also present an opportunity for researchers to find a new pharmacological treatment to selectively block this pathway, effectively destroying such treatment resistant melanoma tumors. 

Today, 92% of all melanoma patients in Israel have been diagnosed with early disease, which improves their chances of survival. In the 1990s, Israel was ranked third in the world after Australia and New Zealand in the annual number of new malignant melanoma patients. Thanks to the Israel Cancer Association’s vigorous activities, a dramatic change for the better has occurred, with Israel ranked only 27th out of the 30 countries with the highest rates in the world.