Written by | Sun Li edited | Miao Xinfang
Neuroblastoma (NB), derived from the embryonic crest, is the most common extracranial solid tumor in children, accounting for 15% of children's lethal tumors. Aggressive NBs tend to respond to initial treatment, but most relapse with a poor prognosis and a survival rate of about 35%. The main cause of treatment failure is relapse and metastasis due to drug resistance.
High-risk neuroblastoma is often accompanied by amplification of the oncogene MYCN and genetic mutations in ALK, which increase the replication pressure of tumor cells (normal cells have no replication pressure). By intervening with cell replication pressures and specifically targeting tumor cells, it brings potential new options for the treatment of high-risk neuroblastoma.
On November 24, 2021, Eynden, a scientist from Ghent University in Belgium, and Hallberg and Palmer, scientists from the University of Gothenburg in Sweden, collaborated to publish an article titled ATR inhibition enables complete tumour regression in ALK-driven NB mouse models at Nature Communications. The paper elucidates that the combination of ATR inhibitors (BAY1895344) and ALK inhibitors (lorlatinib) hinder tumor cell proliferation, induce tumor cell apoptosis, trigger a widespread inflammatory response within tumors, activate the body's immune response, enhance immune cell infiltration, and completely eliminate tumor cells in ALK-driven NB mouse models, providing a feasible new treatment for clinical research on high-risk neuroblastoma.
Through phosphorylation proteomics, the authors found that atr activation is present in ALK-driven NB cells. ATR inhibitors (BAY1895344) inhibit the growth and proliferation of NB cell lines.
ATR inhibitor BAY1895344 inhibits NB cells (ALK-driven NB cell lines: CLB-BAR, CLB-GE, CLB-GAR; Growth of non-ALK-driven NB cell lines: SK-N-AS and IMR-32 (BAY: BAY1895344; criz:crizotinb, ALK inhibitor).
ATR inhibitors inhibit the growth of xenograft tumors in mice. BAY1895344 lorlatinib, alone or in combination, significantly inhibits the growth of ALK-driven transplant tumors, with tumor growth inhibition values (TGI) of 117.6% (lorla), 138.7% (BAY), and 156.9% (combo), respectively.
ATR inhibitors inhibit the growth of xenograft tumors in mice
The combination of ATR inhibitors and ALK inhibitors completely eliminates tumor cells in Alk-driven NB genetically engineered mice. The authors examined the effects of the combination of BAY1895344 and lorlatinib in two NB genetically engineered mouse models (Rosa26_Alkal2; Th-MYCN (n =4) and Alk-F1178S; Th-MYCN (n =4)). After 14 days of medication, compared with the control group, lorlatinib alone can inhibit the growth of tumors in mice, but the tumor does not completely resolve; the combination of drugs makes the tumor cells in mice completely fade, no toxic side effects, and maintain a tumor-free state for a long time, only one mouse found that the tumor had a recurrence in the 100th, 133rd, and 161st days, but the combination of drugs can still eliminate the tumor in the mouse body, and did not produce drug resistance.
Protocol for the application of the combination drug on an Alk/MYCN-driven NB genetically engineered mouse model
Alk/MYCN-driven survival curve of NB genetically engineered mice under different drug uses. Combination medication significantly improves survival.
Compared with the control group (Ctrl), tumor cells in Alk/MYCN-driven NB genetically engineered mice can be completely eliminated after 14 days of combined use.
In NB cells, BAY1895344 targets DNA damage response components, transcription factor E2F-regulated cell cycle genes, G2/M cell cycle checkpoint genes, etc., reducing cell replication pressure and inducing apoptosis; the combination drug can also activate the body's immune system, promote tumor immune infiltration (CD68-positive macrophages are found in tumor cells), and further enhance the killing effect on tumor cells.
This study found that the combination of ATR inhibitor (BAY1895344) and ALK inhibitor (lorlatinib) had a significant inhibitory effect on tumor cells in NB cell lines, xenograft tumor mouse models, and Alk/MYCN-driven NB genetically engineered mouse models, and the combination of drugs at 14 days could completely eliminate tumors in NB mice, and the tumor-free state could be maintained for a long time after treatment. BAY1895344 has entered clinical trials with other solid tumors, suggesting that high-risk NB patients with replication pressure induced by oncogenes are worth trying at ATR inhibitors (BAY1895344).
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