Targeting HERV-K in melanoma: exploring the potential of antiretroviral drugs to overcome resistance and modulate tumor progression

Melanoma, an aggressive form of skin cancer, presents significant treatment challenges. BRAF- mutated melanoma accounts for approximately 50% of cases. Although more malignant, it can be treated with drugs that specifically target BRAF kinase. However, this type of melanoma often develops resistance to BRAF inhibitors rapidly. The human endogenous retrovirus K (HERV-K)—a latent viral sequence within the human genome— has emerged as a potential contributor to melanoma progression and treatment resistance. Reactivated by triggers such as UV radiation or cellular stress, HERV-K is linked to increased tumor aggressiveness and poor prognosis. This study explores the use of antiretroviral drugs to inhibit HERV-K as a novel therapeutic strategy, focusing on their potential to target not only melanoma progression but also resistance mechanisms. Three antiretroviral drugs—lamivudine, doravirine, and cabotegravir—were selected for their efficacy in treating retroviral infections with minimal side effects. Human melanoma cell lines (A375, FO-1, SK-Mel-28, and MeWo) and normal human epithelial melanocytes, used as control to assess drug toxicity in healthy cells, were utilized in the experiments. Techniques, including cell viability assays, migration studies, gene expression analysis, protein expression investigation, and soft agar colony formation tests, were employed to evaluate the impact of these drugs. Additionally, a characterization of the RAF inhibitor-resistant melanoma cell populations (A375R and FO-1R) was conducted, to investigate the different molecular mechanisms of resistance and how they might influence the effectiveness of treatment. The results demonstrated a significant reduction in melanoma cell viability, with cabotegravir showing the most pronounced effects, including apoptosis and ferroptosis induction. These antiretrovirals also modulated key cell cycle regulators, such as cyclins and cyclin-dependent kinases, inhibited tumor cell migration, and reduced anchorage-independent growth—a hallmark of aggressive cancer cells. Furthermore, immune response proteins such as stimulator of interferon genes (STING) and programmed death-ligand 1 (PD-L1) were regulated by the treatments. Notably, the study revealed the efficacy of antiretroviral drugs against four RAF inhibitor (dabrafenib and AZ628) -resistant melanoma cells (A375R and FO-1R). Cabotegravir and doravirine significantly reduced the viability of resistant cells, induced apoptosis, and upregulated tumor suppressor proteins such as p27KIP1 and p16INK4a, effectively halting cell proliferation. A key finding was the suppression of HERV-K expression, which is further elevated in resistant cell populations, suggesting that inhibiting HERV-K may be central to the therapeutic effects observed. While preclinical and clinical studies are needed to confirm the in vivo consistency of these findings, this research highlights the potential of antiretroviral drugs, particularly cabotegravir and doravirine, as promising agents in melanoma therapy. By targeting HERV-K and modulating critical pathways involved in tumor progression and resistance, these drugs open new avenues for the treatment of this challenging disease.