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Therapeutic Vulnerability to ATR Inhibition in Concurrent NF1 and ATRX-Deficient/ALT-Positive High-Grade Solid Tumors
Ming Yuan1, Charles G Eberhart1, Christine A Pratilas2,3
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
Abstract:
Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and the presence of alternative lengthening of telomeres (ALT). We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. Cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), an NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), an 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, with or without a MEK inhibitor 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 in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line demonstrated sensitivity to ATR inhibition, but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors.
Insights
Targeting the ATR pathway shows promise for Neurofibromatosis Type 1 (NF1)-associated tumors with ATRX mutations. ATR inhibitors sensitized specific NF1-deficient glioblastoma and MPNST cells, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neurofibromatosis Type 1 (NF1)-associated solid tumors frequently exhibit ATRX mutations and alternative lengthening of telomeres (ALT).
- Understanding the combined effects of NF1 and ATRX deficiency in malignant solid tumors is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the phenotypic consequences of combined NF1 and ATRX deficiency in malignant solid tumors.
- To evaluate the efficacy of ATR inhibitors, alone or in combination with MEK inhibitors or temozolomide, in NF1-deficient and associated tumor models.
Main Methods:
- Utilized cell lines from NF1-deficient glioblastomas, an NF1-associated ATRX mutant glioblastoma, an NF1-derived sarcoma, and NF1-deficient malignant peripheral nerve sheath tumor (MPNST) lines.
- Treated cancer cells with ATR inhibitors, with or without MEK inhibitors or temozolomide.
- Performed ATRX knockout (KO) and TERC KO, or ATRX knockdown, in specific cell lines to assess their impact on drug sensitivity.
Main Results:
- Combined ATRX and TERC KO induced ALT-like properties and sensitized U251 glioma cells to ATR inhibition in vitro and in vivo.
- ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, regardless of ATRX levels.
- The NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1) and one MPNST cell line (NF90.8) showed sensitivity to ATR inhibition under specific genetic modifications.
Conclusions:
- Targeting the ATR pathway is a feasible therapeutic strategy for a subset of NF1-deficient and associated solid tumors.
- The study highlights the differential sensitivity of various NF1-associated tumor types to ATR inhibition and combination therapies.
