Posted: Tuesday, May 31, 2022
A study conducted by Ren‐Wang Peng, PhD, of Bern University Hospital, University of Bern, Switzerland, and colleagues aimed to identify selective metabolic lethality induced by mutant KRAS in patients with lung cancer. Published in the Journal of Experimental & Clinical Cancer Research, these findings identified a previously unrecognized mechanism in which nucleolar protein 5A (NOP56) and mechanistic target of rapamycin (mTOR) seem to cooperate in the response to oxidative stress.
“These results shed light on the mechanisms underlying KRAS-induced metabolic rewiring, reveal an unanticipated metabolic vulnerability in KRAS-mutant lung cancer, and suggest a new rationale for the treatment of the disease,” concluded the study authors. “Because KRAS alterations are implicated in a broad spectrum of human malignancies, our findings may also be applicable to other lineages of cancer with high frequencies of KRAS alterations.”
The investigators carried out an integrated analysis of RNA interference- and CRISPR-based functional genomic data sets (n = 5). A library of chemical inhibitors for candidates who are synthetic lethal with NOP56 depletion was screened. Using small interfering RNA and short hairpin RNA, pharmacologic inhibition, and CRISPR/Cas9 knockout, functional studies were performed. Cancer cell lines were obtained from the American Type Culture Collection, and PF139 and PF563 lung cancer cells were established from specimens of a 67-year-old female patient and a 75-year-old male patient, respectively.
NOP56 was observed to play an essential role in ribosome biogenesis. Notably, NOP56 induced a metabolic dependency, and its depletion caused synthetic lethal susceptibility to mTOR inhibition. Cancer cells with reduced NOP56 were exposed to higher levels of ROS and relied on mTOR signaling to survive and balance oxidative stress. Ultimately, the co-targeting of NOP56 and mTOR significantly intensified KRAS-mutant tumor cell death both in vitro and in vivo.
Disclosure: The study authors reported no conflicts of interest.