Biology subjects

Rodriguez, F. J.

Publications and source records attributed to Rodriguez, F. J..

3 recordsLinked to original sources

bioRxiv2025

Beyond Cell Cycle Control: CDKN2A Loss Orchestrates NAD⁺ Metabolic Plasticity and NAMPT Inhibitor Sensitivity in Glioblastoma

While CDKN2A loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD homeostasis in CDKN2A-deleted glioblastoma, revealing a previously unrecognized metabolic-genetic interface for rationally revisiting NAD+ targeting strategies, moving beyond the broad inhibition approaches.

cancer biology↗

bioRxiv2024

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 {micro}M). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 {micro}M). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 {micro}M) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

cancer biology↗

bioRxiv2022

Therapeutic vulnerability to ATR inhibition in concurrent NF1 and ATRX-deficient high-grade solid tumors

Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and presence of alternative lengthening of telomeres (ALT). In addition, a potential biologic vulnerability of ALT-positive cancer cells is ATR inhibition, a regulator of homologous recombination. We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. For these experiments, cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), a NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), a NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors (AZD6738 and VE-822), in vitro, with or without a MEK inhibitor (AZD6244, selumetinib) or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition (AZD6738 and VE-822) in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition (AZD6244), irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line (ATRX loss/ALT-positive) demonstrated sensitivity to ATR inhibition (AZD6738), but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in the MPNST cell line ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. Tumors with pre-existing ALT, or that subsequently develop ALT after ATRX downregulation, are particularly vulnerable to this therapeutic approach.

cancer biology↗