Therapeutic Vulnerability to ATR Inhibition in Concurrent NF1 and ATRX-Deficient/ALT-Positive High-Grade Solid Tumors

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.

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

“…The abovementioned connections between HR and ATRX deficiency are also intriguing from a therapeutic point of view. Recent preclinical data revealed an increased DNA-damage response and HR repair deficiency (HRD) in ATRX-deficient tumors, resulting in higher sensitivity to poly (ADP-ribose) polymerase (PARP) 42 , 43 as well as ataxia telangiectasia and Rad3-related (ATR) inhibitors 43 , 44 . PARP inhibitors are emerging new therapeutic options in the treatment of primary and recurrent GB 45 , but further clinical evidence is necessary regarding their utility.…”

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1

“…Less common genetic drivers of NF1-associated high-grade gliomas included TP53 mutation (3/17, 18%), PIK3CA or PIK3R1 mutation (4/17, 24%), PTEN mutation (1/17, 6%), PDGFRA amplification (1/17, 6%), MYCN amplification (1/17, 6%), PPM1D mutation (1/17, 6%), and SETD2 mutation (1/17, 6%). Together, these cooperating genetic alterations may represent additional therapeutic targets beyond MEK inhibition for NF1-associated high-grade gliomas, specifically using small molecule inhibitors of CDK4/6 ( e.g., abemaciclib) and either PARP ( e.g., olaparib) or ATR ( e.g., berzosertib) given the known synthetic lethality in tumors that utilize alternative lengthening of telomeres [ 8 , 10 , 33 ].…”

ATR Inhibitors in Platinum-Resistant Ovarian Cancer

“…demonstrated that increased RS confers sensitivity to ATRis. Several genetic mutations cause alterations in RS elevation that also lead to sensitivity to ATRis, such as BRG1 loss ( SMARCA4 -deficient) [ 96 ], reduced APOBEC3B [ 137 ], MYCN amplification [ 123 ], and so on.…”