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  • In mammals ribonucleotide reductase RNR is a


    In mammals, ribonucleotide reductase (RNR) is a unique enzyme that catalyzes the rate-limiting step of de novo synthesis of deoxyribonucleoside triphosphates (dNTPs).7, 8 Mammalian RNR consists of two homodimer subunits: the large catalytic dimer RRM1 and the small regulatory dimer RRM2 or RRM2B. Another study demonstrated that MEK1/2 inhibitor pimasertib enhanced the efficacy of gemcitabine in pancreatic cancer by MDM2-mediated polyubiquitination of RRM1 via proteasomal degradation. Nonetheless, tumors could exert resistance to BRAF-MEK inhibitors through a strong reactivation of ERK protein caused by several different mechanisms.11, 12, 13 As a result, a novel, selective, and ATP-competitive ERK1/2 inhibitor, SCH772984, has been developed. Despite negative feedback activation up to and including phospho-ERK, SCH772984 has a long-lasting ability to inhibit the catalytic activity of ERK and block the signal transduction between ERK and RSK. Targeting ERK is more effective than targeting MEK, because ERK inhibitors can effectively overcome the resistance of tumor Rucaparib free base synthesis to MEK inhibitors. A previous study found that biopsy-accessible breast tumor samples from patients treated with everolimus displayed an increased activation of the mitogen-activated protein kinase (MAPK) pathway in an S6K-PI3K-Ras feedback loop-dependent manner. We aimed to investigate whether ERK activation contributes to the everolimus resistance in RCC and whether the inhibition of ERK signal extends the efficacy of everolimus, and we aimed to highlight the molecular mechanisms underlying the synergistic efficacy of everolimus-ERK inhibitor combination for the treatment of RCC.
    Discussion Everolimus, similar to other PI3K or mTOR inhibitors, has been approved by the FDA for clinical therapy, as the PI3K-AKT-mTOR pathway is frequently dysregulated in a broad spectrum of cancers. However, the antitumor activities of these inhibitors are limited due to the pro-tumorigenic aberrations in other signaling networks. Hence, a rational combination therapy is required to optimize the efficacy of everolimus. Thus, some clinical trials tend to concurrently block the mTOR and MAPK pathways in order to combat the adaptive and innate resistance.24, 25, 26 Regardless of different efficiencies of combination strategies, convincing mechanism-based evidence is lacking to conclude the concurrent blockade of mTOR and MAPK signaling. In this study, we identified a novel combination strategy for RCC, in which everolimus and an ERK inhibitor synergistically inhibit the growth of cancer through the attenuation of dNTP pools by downregulating the levels of RRM1 and RRM2 transcripts. Furthermore, mTORC1, the target of everolimus, promotes glucose, lipid, and nucleotide metabolism in mammals. A recent study established that mTORC1 increases the transcriptional expression of MTHFD2 in an ATF4-dependent manner, thereby inducing the mitochondrial tetrahydrofolate cycle that provides one-carbon units for de novo purine synthesis. Nevertheless, only a few studies have addressed the impact on the metabolism of the tumor cells. This study explored the mechanism underlying the synergistic effect of everolimus-ERK inhibitor combination with respect to tumor metabolism. As expected, the combination of everolimus and ERK inhibitor synergistically downregulates some of the dNTPs, such as dAMP, adenosine, UMP, and dGMP. Subsequently, the combination of everolimus and ERK inhibitor decreases the recruitment of E2F1 to the promoter of RRM1 and RRM2, which, in turn, results in E2F1-mediated transcriptional inhibition of RRM1 and RRM2. Consequently, the downregulated RRM1 and RRM2 attenuate the dNTP pools and inhibit the proliferation of RCC cells by suppressing the G1-S transition. Interestingly, our study identified RRM1 and RRM2 as the funnel molecules that overlap in the mTOR- and ERK-signaling pathways. The RRM1 and RRM2 enzyme are crucial for RNR in normoxia to maintain DNA replication due to their critical role in the homeostasis of dNTPs. The dNTPs are required for DNA synthesis in the G1 to S phase. Similarly, E2F1 plays a pivotal role in the transition of G1 to S phase, and it regulates the expression of several genes required for passage into the S phase. Consistent with the current insights on RCC cells, CG-5, a pan-Glut inhibitor, abrogated the resistance to gemcitabine by decreasing the expression of RRM2 through E2F1-mediated transcriptional inhibition in pancreatic cancer cells. In addition to these mechanistic insights, high RRM1 and RRM2 expressions were correlated with poor prognosis in patients with pancreatic cancer and lung adenocarcinoma treated with gemcitabine, and the downregulation of these molecules increased the chemosensitivity of pancreatic cancer cells to gemcitabine.32, 33 Also, RRM1 and RRM2 predict the prognosis and act as potential therapeutic targets in patients with multiple myeloma and glioblastoma.