Hepatoblastoma (HB) is the most common pediatric liver cancer. While standard cisplatin-based therapy cures ∼80% of patients, resistance remains a major challenge, with no standard second-line treatment. This study aimed to identify new therapeutic options for cisplatin-resistant HB. Fourteen HB cell lines and one pediatric hepatocellular carcinoma cell line were molecularly profiled. Eight cell lines were screened with 101 compounds and 58 combinations in monolayer cultures. The most synergistic combination was further validated in two low-passage patient-derived primary HB cultures and 12 HB spheroid models. In vivo efficacy was evaluated in cisplatin-resistant subcutaneous (n = 2) and orthotopic (n = 1) HB xenografts, and a liver-specific MYC-driven HB-like model. Mechanistic analyses were performed using transcriptomics, DNA damage, and apoptosis assays. Cell lines recapitulated key HB genomic alterations and mainly represented the cisplatin-resistant liver progenitor transcriptomic subtype, characterized by upregulated DNA repair pathways, potentially contributing to chemoresistance. ATR was identified as a critical target for overcoming resistance. The potent ATR inhibitor elimusertib demonstrated strong synergy with cisplatin in 2D and 3D cultures. In vivo, the elimusertib/cisplatin combination significantly suppressed tumor growth in xenografts, with manageable toxicity, inducing tumor cell death through enhanced DNA damage and p53 activation. The combination also showed antitumor efficacy in the MYC-driven HB-like model, which mirrors the cisplatin resistance and DNA repair features of the human liver progenitor HB subtype. Additional in vitro studies suggested that elimusertib synergizes with other standard HB chemotherapies and inhibits mTOR. ATR mediates cisplatin resistance in HB. The combination of elimusertib and cisplatin demonstrated preclinical efficacy across patient-derived cultures and multiple in vivo HB models, supporting its potential as a promising therapy for cisplatin-resistant HB. Chemoresistance significantly reduces survival in patients with hepatoblastoma, highlighting the need for new therapies. In this study, we found that blocking ATR with the drug elimusertib synergizes with cisplatin, strongly reducing tumor growth in diverse preclinical models, including cell cultures and mouse models of cisplatin-resistant hepatoblastoma. These results highlight a promising new approach to improve outcomes for children with cisplatin-resistant hepatoblastoma and support further clinical evaluation.

DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.

Pediatric hepatocellular carcinoma (HCC) is a rare malignant liver tumor affecting children and adolescents and occurring either sporadically or in the context of underlying liver disease. In this review, we detail the epidemiology of pediatric HCC with a focus on predisposing factors including hepatic or systemic disease, genetic disorders, and familial cancer syndromes. We summarize existing research on the pathophysiology of pediatric HCC, including molecular mechanisms of oncogenesis, highlighting unique disease features differentiating pediatric HCC from adult HCC. We then survey the landscape of therapeutic options for pediatric HCC, including novel therapeutics. Lastly, we discuss the pathologic spectrum upon which pediatric HCC is postulated to exist, ranging from hepatoblastoma to HCC and including the hybrid entity hepatocellular neoplasm not otherwise specifed (HCN-NOS). In summary, we highlight the key clinical and molecular features of pediatric HCC that may inform future research and novel approaches to the clinical care of these patients.

Two percent of pediatric malignancies arise primarily in the liver; roughly 60% of these cancers are hepatoblastoma (HB). Despite the rarity of these cases, international collaborative efforts have led to the consistent histological classification and staging systems, which facilitate ongoing clinical trials. Other primary liver malignancies seen in children include hepatocellular carcinoma (HCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), undifferentiated embryonal sarcoma of the liver (UESL), and hepatocellular neoplasm not otherwise specified (HCN-NOS). This review describes principles of surgical management of malignant pediatric primary liver tumors, within the context of comprehensive multidisciplinary care.