Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I
Journal Title
Translational Research
Publication Type
Research article
Abstract
DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. Given recent evidence of Dicer's role as a haploinsufficient tumor suppressor regulating RNA polymerase I (Pol I), Pol I inhibition could abrogate mutant Dicer-mediated accumulation of stalled polymerases to trigger apoptosis. Hence, we developed a novel subpleural orthotopic PPB patient-derived xenograft (PDX) model that retained both RNase IIIa and IIIb hotspot mutations and recapitulated the cardiorespiratory physiology of intra-thoracic disease, and with it evaluated the tolerability and efficacy of first-in-class Pol I inhibitor CX-5461. In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.
Publisher
Elsevier
Keywords
Humans; *RNA Polymerase I/genetics/metabolism; Tumor Suppressor Protein p53/genetics; *Pulmonary Blastoma/genetics/metabolism/pathology; Carcinogenesis; Ribonuclease III/genetics/metabolism; DEAD-box RNA Helicases/genetics/metabolism; Cx-5461; Dicer1; Pleuropulmonary blastoma; RNA polymerase I; RNase IIIa; RNase IIIb; patient-derived xenograft model
Department(s)
Laboratory Research
PubMed ID
36921796
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Creation Date: 2023-11-14 12:42:06
Last Modified: 2023-11-14 12:43:26
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