The Graeber Laboratory at UCLA discovered a novel mechanism for treating melanoma using ferroptosis, a type of programmed cell death, that shows promise against therapy resistance.
BACKGROUND: Melanoma is a highly aggressive skin cancer that spreads throughout the body and can be fatal if left untreated. Therapies for melanoma range from immunotherapy to more targeted drug therapies, such as BRAF inhibitors, that target mutated proteins involved in cancer cell proliferation. Treatment for melanoma, however, still poses significant challenges due to its propensity for therapy resistance. Conventional therapies, including targeted kinase inhibitors, often encounter limitations as melanoma cells evolve resistance mechanisms, such as manipulation of cell proliferation pathways through increased BRAF and MAPK activity. This resistance can emerge either inherently or as a response to treatment strategies like kinase inhibition. Notably, heightened MAPK signaling, coupled with alterations in factors like MITF levels and metabolic pathways, contributes to the adaptive plasticity of melanoma cells, thwarting conventional therapeutic approaches.
INNOVATION: The Graeber Lab uses an innovative approach to treat melanoma harnessing ferroptosis, a distinctive form of cell death triggered by iron-dependent accumulation of lipid reactive oxygen species. By targeting ferroptosis using small molecule drugs, melanoma cells exhibiting augmented MAPK signaling display heightened susceptibility to ferroptotic cell death. Notably, their work identified a pivotal link between increased MAPK pathway activity and enhanced sensitivity to ferroptotic induction, particularly in melanoma cells resistant to conventional therapies. With this discovery, pro-ferroptotic agents provide a novel therapeutic mechanism to target melanoma plasticity and survival mechanisms to enhance anti-tumor effects of targeted and immune therapies.
POTENTIAL APPLICATIONS:
- Melanoma treatment
- Combination therapy with immunotherapy for enhanced anti-cancer effects
- Pro-ferroptotic drug development
ADVANTAGES:
- No evidence of dedifferentiation in melanoma cells treated with ferroptosis drugs
- High sensitivity/precision of ferroptosis treatment of melanoma
DEVELOPMENT-TO-DATE: Research has been done in vitro (cell lines).