ATM Inhibition Sensitizes ALT Neuroblastomas to Chemotherapy

The unlimited ability of cancer cells to proliferate is achieved by maintaining telomeres via either telomerase activation or recombination-based alternative lengthening of telomeres (ALT). ALT is more common in cancers of neuroepithelial and mesenchymal origin and is activated in approximately 23% of high-risk neuroblastomas. ALT neuroblastomas are associated with poor response to chemotherapy and patients who relapse or progress after front-line therapy are highly unlikely to survive. Using ALT neuroblastoma cell lines, Koneru and colleagues showed that ALT cells exhibit chemoresistance to standard chemotherapy agents (temozolomide and irinotecan) used to treat neuroblastoma both in vitro and in vivo compared with non-ALT controls. RNA sequencing revealed ATM and ATR–BRCA signaling pathways to be enriched in ALT neuroblastoma cells, which also had significantly increased markers of double-strand DNA breaks compared with cells with normal telomerase activation. Immunoblotting revealed constitutive phosphorylation of ATM and CHK2 in ALT neuroblastoma cell lines and patient-derived xenografts. Induction of telomere dysfunctional foci activated ATM, conferring resistance to temozolomide. Subsequent RNAi-mediated depletion or small molecule–mediated inhibition of ATM recovered sensitivity to temozolomide and irinotecan in ALT neuroblastoma cell lines, but not in telomerase-positive models in vitro and in vivo. Moreover, pharmacologic inhibition of ATR had no discernable effect on response to these drugs in ALT cells, suggesting ALT-mediated resistance to chemotherapy is ATM-specific. These findings provide a rationale for clinical evaluation of ATM inhibition in combination with standard therapies to improve outcomes in ALT-positive neuroblastoma.

Koneru B, Farooqi A, Nguyen TH, Chen WH, Hindle A, Eslinger C, et al. ALT neuroblastoma chemoresistance due to telomere dysfunction–induced ATM activation is reversible with ATM inhibitor AZD0156. Sci Transl Med 2021;13:eabd5750.

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