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Radioresistance is a major obstacle for the successful therapy of many cancers, including non-small cell lung cancer (NSCLC). To elucidate the mechanism of radioresistance of NSCLC cells and to identify key molecules conferring radioresistance, the radioresistant subclones of p53 wild-type A549 and p53-deficient H1299 cell cultures were established. The transcriptional changes between parental and radioresistant NSCLC cells were investigated by RNA-seq. In total, expression levels of 36,596 genes were measured. Changes in the activation of intracellular molecular pathways of cells surviving irradiation relative to parental cells were quantified using the Oncobox bioinformatics platform. Following 30 rounds of 2 Gy irradiation, a total of 322 genes were differentially expressed between p53 wild-type radioresistant A549IR and parental A549 cells. For the p53-deficient (H1299) NSCLC cells, the parental and irradiated populations differed in the expression of 1628 genes and 1616 pathways. The expression of genes associated with radioresistance reflects the complex biological processes involved in clinical cancer cell eradication and might serve as a potential biomarker and therapeutic target for NSCLC treatment.

The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.

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