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Tumor repopulation during cycles of radiotherapy limits the radio-response in ensuing cycles and causes failure of treatment. It is thus of vital importance to unveil the mechanisms underlying tumor repopulating cells. Increasing evidence suggests that a subpopulation of drug-tolerant persister cancer cells (DTPs) could survive the cytotoxic treatment and resume to propagate. Whether these persister cells contribute to development of radio-resistance remains elusive. Based on the genetic profiling of DTPs by integrating datasets from Gene Expression Omnibus database, this study aimed to provide novel insights into tumor-repopulation mediated radio-resistance and identify predictive biomarkers for radio-response in clinic. A prognostic risk index, grounded on four persister genes (LYNX1, SYNPO, GADD45B, and PDLIM1), was constructed in non-small-cell lung cancer patients from The Cancer Genome Atlas Program (TCGA) using stepwise Cox regression analysis. Weighted gene co-expression network analysis further confirmed the interaction among persister-gene based risk score, radio-response and overall survival time. In addition, the predictive role of risk index was validated  in vitro  and in other types of TCGA patients. Gene set enrichment analysis was performed to decipher the possible biological signaling, which indicated that two forces behind persister cells, stress response and survival adaptation, might fuel the tumor repopulation after radiation. Targeting these persister cells may represent a new prognostic and therapeutic approach to enhance radio-response and prevent radio-resistance induced by tumor repopulation.

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation