Author(s): Joshua Knight, Allison Stevens, Madison Hawkins, Alec Morimoto, Ben Shaver, Taylor Steins, Danielle Johnson-Erickson
Mentor(s): Gennie Parkman
Institution Weber
Melanoma, a highly aggressive skin cancer, remains a significant clinical challenge due to its resistance to conventional therapies and the development of resistance to targeted treatments, particularly those involving BRAF and MEK inhibitors. The mechanistic target of rapamycin (mTOR) pathway, a critical regulator of cell growth, metabolism, and survival, has emerged as a promising target in melanoma therapy. Dysregulation of mTOR signaling has been implicated in melanoma progression, metastasis, and resistance to treatment. Our study examined the role of mTOR signaling in the differential effects of FLASH, or ultra-high dose, radiation compared to conventional radiation in melanoma. FLASH radiotherapy is characterized by its ability to deliver high doses of radiation to tumor tissues while minimizing damage to surrounding healthy tissues. We found that FLASH radiation significantly upregulated mTOR and its regulatory protein, Raptor, suggesting mTOR’s involvement in the unique biological response to FLASH. mTOR is known to promote PD-L1 expression on cancer cells and enhance immune-suppressive lymphocyte infiltration via interferon and TGF-β signaling. Based on these findings, we explored the potential of combining FLASH radiation with immune checkpoint inhibitors, specifically anti-PD-1, to improve melanoma treatment outcomes. Preliminary in vivo experiments revealed that mice treated with FLASH radiation and anti-PD-1 had increased survival rates, indicating a potential therapeutic benefit. Further analysis showed elevated levels of phosphorylated mTOR (Ser2448) and its downstream substrates, suggesting mTOR's role in mediating this response. These results suggest that mTOR not only regulates immune responses in cancer but may also influence response to FLASH radiation. While we have validated our findings using immunoblotting, further studies are needed to fully elucidate the underlying mechanisms of mTOR’s role in the response to FLASH radiation.