Hope for New Apoptotic Regulatory Pathway in Treating Non-Melanoma Skin Cancers

Researchers discovered compelling evidence that the mechanistic target of rapamycin complex 2 (mTORC2) directs ultraviolet B [UVB]–induced apoptosis by regulating the expression of NOXA downstream of the transcription factor forkhead box O3 [FOXO3a]. Their findings were published in the journal Cellular Signalling.

“This fascinating study highlights the importance of single pathways and the hope in developing targeted agents in the treatment of non-melanoma skin cancers. [It also] further highlights how important the phosphatidylinositol-3-kinase (PI3K)/Akt pathway is in promoting skin cancer pathways,” Hung Doan, MD, PhD, an assistant professor of dermatology at MD Anderson Cancer Center and UTHealth McGovern Medical School, told Cancer Network.

Feehan et al hypothesized that, in the context of mTORC2 inhibition, the UVB-induced expression of NOXA and TRAIL would result in apoptosis in a FOXO3a-dependent manner. They observed that, in spontaneously immortalized human kertinocytes (HaCaT cells), TRAIL and NOXA expression heightened in cells exposed to UVB, as well as the TOR kinase inhibitor Torin 2.

Akin to the knockdown of FOXO3a, NOXA knockdown resulted in the reversal of sensitization to UVB-induced apoptosis resulting from mTORC2 inhibition. Surprisingly, however, the loss of TRAIL via either knockdown or knockout promoted expression of nuclear FOXO3a, thus maintaining apoptosis.

Notably, the researchers determined that these results are not caused by faulty death receptor signaling in HaCaT cells, as the cells experience extrinsic apoptosis in response to recombinant-TRAIL treatment. They also found that TRAIL knockout cells were sensitized to recombinant TRAIL-induced apoptosis versus wild-type HaCaT cells, with the greatest increase transpiring in the setting of mTORC2 inhibition.

“These studies demonstrate that UVB generates a unique FOXO3a-dependent cell death response when mTORC2 is inhibited, leading to increased caspase-dependent apoptosis that is regulated at least in part by NOXA-mediated intrinsic apoptosis but not by TRAIL [TNF-related apoptosis-inducing ligand] –dependent extrinsic apoptosis,” the authors concluded.

Doan noted that these findings may have future implications for the treatment of non-melanoma skin cancers. “In the contemporary treatment of NMSCs [non-melanoma skin cancers] and precancerous lesions, we employ a variety of local topical medications, local destructive methods, and ultimately surgical interventions. [These findings add] that potentially targeting a specific pathway may allow for the development of yet another novel modality…Furthermore, the study showed that instead of UVB causing changes leading to cancer, UVB, in this case, resulted in the expression of a pro-apoptotic protein, NOXA, rendering cells more susceptible to cell death.”

"The authors demonstrate a novel apoptosis regulatory pathway via the mTORC2/FOXO3a axis of the PI3K/Akt pathway in sensitizing keratinocytes to UVB radiation. Studies such as this highlight the need to continue to further our knowledge regarding the intracellular mechanisms which mediate carcinogenesis,” Doan added.

According to Doan, one weakness of the study is that it was carried out in keratinocyte cells. Future studies should focus on altered cells and potentially animal studies if the laboratory studies found compelling, consistent results, he said. 

In a separate interview with Cancer Network, Shawn Demehri, MD, PhD, a medical oncologist of dermatology at Massachusetts General Hospital Cancer Center, noted the implications of these findings. “This is an interesting study that adds to our understanding of the mechanism of cell death upon UV exposure. Non-melanoma skin cancers are the most common cancer types. Ultraviolet radiation (UV) is the driver of skin cancers. Therefore, the mechanism to promote the death of skin cells exposed to UV would potentially have a beneficial impact on removing UV-damaged cells and prevent them from progressing to cancer,” he said.

Demehri went on to note several positive and negative aspects of the study. “The study of UV-damaged skin cells and how to promote their death upon this damage is very relevant to skin cancer prevention and treatment. The limitation of this study [is] the use of cell line, which will require further validation in live organisms-animal models and eventually humans. In addition, the findings are focused on intervening in the cellular response to concurrent UV exposure. However, most skin cancers develop due to years of UV exposure prior to the time that any intervention could be devised,” he said.