Biology subjects

Borenas, M.

Publications and source records attributed to Borenas, M..

4 recordsLinked to original sources

bioRxiv2025

ALK/ATR combination therapy is effective in neuroblastoma mouse tumors driven by MYCN

Summary paragraphOne of the key features of high-risk neuroblastoma (NB) is MYCN-amplification. While MYCN is still regarded as therapeutically challenging despite intensive efforts to find targeting compounds, inhibitors against Anaplastic Lymphoma Kinase (ALK) are now being evaluated among ALK-driven NB patients with promising results. There is a pressing need to find alternative treatment regimens for ALK naive MYCN-amplified patients, as current regimes are accompanied by significant mortality and morbidity. Here we show that genetically removing Alk in the Th-MYCN-driven engineered NB mouse model (GEMM) resulted in decreased tumor penetrance, and survival of Th-MYCN homozygote GEMMs, suggesting that Alk activity contributes to aggressiv e neuroblastoma development in this model. Given the high levels of replication stress induced in Th-MYCN tumors, we employed inhibitors of Ataxia Telangiectasia Rad3 related (ATR), combining ATR and ALK inhibition in a 14-day treatment regime, and comparing with ATR inhibitor monotreatment. Th-MYCN tumor bearing mice that received ATRi/ALKi combination treatment exhibited significantly increased survival compared to ATRi alone, that was sustained over time. Together, our data highlight a potentially effective treatment option for the currently challenging category of MYCN-amplified NB patients lacking ALK mutations.

cancer biology↗

bioRxiv2024

Spatial transcriptomics exploration of the primary neuroblastoma microenvironment unveils novel paracrine interactions

High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this gap, we profiled untreated and chemotherapy-treated high-risk neuroblastomas from 2 patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p-gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokine CCL18 and its receptor PITPNM3 was predicted between these cells and we experimentally demonstrated that CCL18 increases neuroblastoma cell migration. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical-like cells expressed the ALK ligand ALKAL2 and were predicted to communicate with neighboring ALK expressing cancer cells. We demonstrated a unique developmental pattern of adrenal medulla-specific expression of ALK and adrenocortical-specific expression of ALKAL2, suggesting a role of these signaling interactions in neuroblastoma carcinogenesis.

cancer biology↗

bioRxiv2024

RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma.

High-risk neuroblastoma is characterized by MYCN amplification and high MYCN or MYC gene expression. These patients have a poor prognosis and there is an urgent need for more effective drugs. While strategies to develop inhibitors that directly target the MYC proteins have remained largely unsuccessful, recent preclinical studies have identified ATR, a key protein of the DNA damage response, as a promising alternative therapeutic target. Here we identified a strong RUVBL1 and RUVBL2 signature in transcriptomics data derived from different MYCN-driven mice tumors treated with ATR inhibitors. The RUVBL proteins form a complex with ATPase activity that has broad cellular functions and we demonstrate that pharmacological inhibition of this protein complex results in a strong reduction of MYC signaling, cell cycle arrest, DNA damage and apoptosis. We confirmed the association with MYCN and identified the RUVBL genes as independent prognosticators in human primary neuroblastoma data.

cancer biology↗

bioRxiv2024

FGFR2 promotes resistance to ALK tyrosine kinase inhibitors and its inhibition acts synergistically with lorlatinib in the treatment of ALK-expressing neuroblastoma

Anaplastic Lymphoma Kinase inhibitors (ALK TKIs) are approved for the treatment of ALK-positive non-small cell lung cancer (NSCLC) and are in clinical trial for ALK-aberrant high-risk neuroblastoma (NB) patients, particularly loratinib. However, resistance to ALK inhibitors can occur in patients, via the activation of bypass-signalling pathways, and there is a need to identify these mechanisms as well as drugs that inhibit them to design therapeutic approaches that prevent resistance, and to treat ALK TKI relapsed/refractory disease. Using genome-wide CRISPR-Cas9 overexpression screens, we identified and validated FGFR2 as a desensitizer to lorlatinib in aberrant ALK-expressing high-risk NB. FGFR2 and FGFR2-associated pathways are up-regulated in lorlatinib-resistant NB cells. Moreover, high-throughput screens using a library of 1,430 FDA approved drugs identified kinase inhibitors including those targeting FGFR2 as efficacious in reducing the survival of lorlatinib resistant NB cells. Hence, the FGFR pathway was investigated as a therapeutic target applying the pan-FGFR inhibitor erdafitinib or the multi-kinase inhibitor ponatinib, resulting in reduced survival of lorlatinib-resitant cells in comparison to their lorlatinib-sensitive counterparts. Moreover, both FGFR inhibitors act synergistically with lorlatinib in vitro and in vivo, using patient-derived xenografts (PDXs) and genetically engineered models (GEMM) of ALK-expressing NB. FGFR2 mRNA expression also correlate with a poorer prognosis for NB patients, regardless of sub-type, suggesting that a broader range of patients may benefit from FGFR inhibitors. Overall, our data suggests that FGFR2 potentially plays roles in lorlatinib resistance in NB and that combined pharmacological inhibition of ALK and FGFR constitutes a therapeutic approach to treat high-risk NB.

cancer biology↗