Naturally occurring peptide can reverse drug resistance in melanoma

Melanoma is one of the deadliest forms of skin cancer, due in large part to its ability to rapidly develop resistance to treatment. Now, researchers at the University of California San Diego have identified a naturally occurring peptide - a small protein fragment composed of linked amino acids - that may help counter one of cancer's most dangerous survival strategies.

The researchers report that catestatin (CST) - a bioactive peptide derived from the Chromogranin A (CgA) protein - significantly slowed melanoma growth, reduced melanoma's ability to spread, and restored sensitivity in drug-resistant melanoma cells.

The findings suggest that CST could serve as the foundation for a new class of peptide-based therapies aimed at treating advanced and therapy-resistant melanoma.

Melanoma is particularly dangerous because tumor cells can adapt and become resistant to therapy. Our research shows that CST can disrupt those resistance pathways and push melanoma cells back toward a more treatable state."

Sushil K. Mahata, PhD, professor of medicine at UC San Diego School of Medicine and research physiologist at the VA San Diego Healthcare System

"In the era of small-molecule inhibitors and immunotherapy, the therapeutic potential of peptides remains relatively underexplored," added first author Satadeepa Kal, PhD, a postdoctoral researcher at UC San Diego School of Medicine. "Our work demonstrates that peptide-based therapies may offer a powerful strategy not only against melanoma and drug resistance, but potentially against other cancers and complex metabolic diseases as well."

Unlike many conventional cancer therapies, which broadly target rapidly dividing cells and can produce substantial side effects, peptides such as CST can be engineered to interact with highly specific molecular pathways. This precision may enable selective targeting of tumor cells while minimizing damage to healthy tissue.

Key findings

• CST significantly reduced tumor growth and overall tumor burden in both human melanoma cell lines and mouse models.
• The peptide suppressed melanoma-cell migration and invasive behavior, suggesting a potential role in limiting metastasis.
• CST reprogrammed melanoma cells that had become resistant to standard targeted therapies, reducing the activity of genes associated with cancer survival and drug resistance.
• The peptide selectively targeted melanoma cells while sparing normal skin cells, highlighting a potential safety advantage over conventional treatments.
• In patient samples, natural CST levels declined as melanoma progressed to more aggressive stages, suggesting that loss of the peptide may help tumors evade the body's intrinsic protective mechanisms.

Beyond melanoma, the team believes CST's broader biological functions may have implications for additional therapeutic applications. Because the peptide originates from CgA - a protein involved in cardiovascular, metabolic, immune and neuroendocrine regulation - researchers are also exploring its potential roles in heart disease, metabolic disorders and neurodegenerative conditions such as Alzheimer's disease.

Although additional preclinical and clinical studies will be required, the findings point toward a promising new therapeutic strategy for cancers that no longer respond to current treatments.

The study, published in Oncogenesis, was led by Kal and Mahata. It was funded, in part, by grants from the National Institutes of Health (AG080246, AG078635, and AG091126) and the U.S. Department of Veteran's Affairs (RX004398, I01BX004848 and IBX005224). Mahata is founder of CgA Therapeuticals, Inc. and co-founder of Siraj Therapeutics. Mahata, Kal, and Soo Jin Park are coinventors on a patent related to this work.