Comprehensive analysis of ribosomal S6 protein kinase family genes as prognostic biomarkers in pan-cancer

The ribosomal S6 kinase (RSK) gene family consists of four genes: RPS6KA1, RPS6KA3, RPS6KA2, and RPS6KA6. The roles of these genes in cancer have received widespread attention. Our previous research found that RPS6KA6 may have both oncogenic and tumor-suppressive functions in cancer. It is still unclear whether this phenomenon also occurs for other RSK family members. Here, based on the TCGA database, we systematically evaluated the potential of RSK family genes as prognostic biomarkers for pan-cancer using multiple statistical methods (including the Wilcoxon test, Cox regression, Kaplan-Meier survival analysis, and correlation analysis, implemented through the R language). The prognostic results were verified using the independent databases PrognoScan and Kaplan-Meier Plotter. Our research found that RPS6KA1, RPS6KA3, RPS6KA2, and RPS6KA6 were highly expressed in 9, 5, 2, and 2 types of cancer, respectively. In addition, they were also lowly expressed in 6, 3, 13, and 12 types of cancer, respectively. RSK expression was significantly correlated with the prognosis of some cancers, tumor microenvironment, stemness score, tumor mutation burden, and microsatellite instability. In the drug sensitivity analysis, RPS6KA1 expression showed a positive association with fludarabine, cyclophosphamide, and 8‑chloro-adenosine. Similarly, elevated expression of RPS6KA3 was correlated with sensitivity to RO-4987,655, TAK-733, PD-0325,901, and pimasertib. Conversely, higher levels of RPS6KA2 were inversely associated with responses to AMONAFIDE, malacid, and RX-3117, while increased RPS6KA6 expression was linked to reduced sensitivity to RG-7741. In conclusion, our findings underscore that RSK family members cannot be simply categorized as pure “oncogenes” or “tumor suppressors”; their prognostic roles are highly cancer-type specific.