Abstract It is becoming increasingly clear that dysregulation of protein synthesis contributes to a range of diseases characterized by tissue overgrowth. These include arterial stenosis, cardiac hypertrophy, hamartomas, and cancer. The central hub for the regulation of protein synthesis is the ribosome, where the key signaling pathways downstream of RAS, MYC, and phosphatidylinositol‐3‐kinase (PI3K) converge to confer exquisite, coordinated control of ribosome synthesis and function. Such cooperation ensures strict regulation of protein synthesis rates and cell growth. This review will focus on the role the PI3K/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway plays in regulating ribosome function during both health and disease, its interaction with the other key growth regulatory pathways activated by RAS and MYC, and the therapeutic potential for targeting this network. © 2011 IUBMB IUBMB Life, 63(2): 79–85, 2011
<p>Exposure-response relationship between CX-5461 levels and rDNA transcription rate in normal PBMCs</p>
<p>Pharmacokinetics analysis of CX-5461 in patients with advanced hematological disease</p>
STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in
<div>Abstract<p>RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m<sup>2</sup>, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.</p>Significance:<p>CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in <i>TP53</i> wild-type and mutant malignancies.</p><p><i>This article is highlighted in the In This Issue feature, p. 983</i></p></div>
Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.
<p>All Supplementary Tables</p>
<p>All Supplementary Methods and associated references</p>
Somatic cells have ~200 hundred copies of ribosomal RNA (rRNA) genes (rDNA) per haploid genome of which only a fraction are transcribed by RNA polymerase I (Pol I) at any given time. Thus regulation of rDNA transcription involves controlling both the number of active genes as well as the rate of transcription per gene. How and why a majority of rDNA are silenced is unclear but recent studies indicate that in addition to controlling rRNA synthesis, rDNA silencing plays an essential role in maintaining the genetic stability of rDNA repeats and influences cellular events such as aging and senescence. In this review we discuss the role of the cytoarchitectural transcription factor UBF in determining and maintaining the active (euchromatic) state of rDNA in mammals. In particular we discuss evidence to suggest that UBF dynamically regulates the active rRNA gene pool during differentiation and malignancy.
