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Neuro-Oncology, Apr 11 2025, noaf096 | https://doi.org/10.1093/neuonc/noaf096
BCOR loss promotes both retinoblastoma growth and susceptibility to IGF1R inhibition
Su-Chan Lee 1, Satoshi Nakata 2, Lujain Alaali 1, Kaixuan Wang 3, Pei-Chi Tsai 3, Khoa Pham 1, Brent A Orr 4, Quynh T Tran 4, Laura Asnaghi 1,5, Eric Raabe 5, Charles G Eberhart 1,6
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2Department of Neurosurgery, Gunma University, Maebashi, Japan.
3Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland.
4Department of Pathology, St. Jude Children's Hospital, Memphis, Tennessee.
5Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Corresponding author: Dr. Charles Eberhart
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2Department of Neurosurgery, Gunma University, Maebashi, Japan.
3Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland.
4Department of Pathology, St. Jude Children's Hospital, Memphis, Tennessee.
5Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Corresponding author: Dr. Charles Eberhart
Abstract
Background: BCL-6 corepressor (BCOR) loss of function alterations are common in clinically aggressive retinoblastoma. The study aim was to determine if BCOR loss promotes the growth and dissemination of retinoblastoma cells, and identify the pathways it regulates in these retinal tumors of childhood.
Methods: Gain and loss of function strategies were used to modulate BCOR levels in a panel of retinoblastoma cell lines, and the effects on proliferation, clonogenicity, apoptosis and migration were assessed in vitro and in murine xenograft models.
Results: BCOR knockdown or knockout in retinoblastoma lines with high protein levels increased tumor growth, invasion, clonogenicity and chemoresistance in vitro, while increased expression in low BCOR lines slowed growth. Growth of retinoblastoma xenografts was similarly sensitive to BCOR gain or loss. BCOR reduction resulted in upregulation of IGF1 and activation of IGF1 receptor (IGF1R) signaling, and the effects of IGF1R inhibition were dependent on BCOR level. In vitro, reduction of retinoblastoma growth and induction of apoptosis by the IGF1R inhibitors linsitinib and AEW541 was also significantly stronger in cells with low BCOR as compared to controls. Both linsitinib and AEW541 suppressed colony formation in a dose-dependent manner in BCOR knockout or knockdown cells. Finally, high BCOR levels rendered retinoblastoma xenografts insensitive to linsitinib.
Conclusions: Loss of BCOR function is associated with more aggressive retinoblastoma cell line growth and chemoresistance, at least in part due to increased IGF1R signaling. Inhibiting IGF1R pharmacologically had a marked anti-tumor effect in aggressive retinoblastoma lacking BCOR, suggesting it as a new therapeutic target, although this still needs to be confirmed in clinical samples with BCOR mutations.
Methods: Gain and loss of function strategies were used to modulate BCOR levels in a panel of retinoblastoma cell lines, and the effects on proliferation, clonogenicity, apoptosis and migration were assessed in vitro and in murine xenograft models.
Results: BCOR knockdown or knockout in retinoblastoma lines with high protein levels increased tumor growth, invasion, clonogenicity and chemoresistance in vitro, while increased expression in low BCOR lines slowed growth. Growth of retinoblastoma xenografts was similarly sensitive to BCOR gain or loss. BCOR reduction resulted in upregulation of IGF1 and activation of IGF1 receptor (IGF1R) signaling, and the effects of IGF1R inhibition were dependent on BCOR level. In vitro, reduction of retinoblastoma growth and induction of apoptosis by the IGF1R inhibitors linsitinib and AEW541 was also significantly stronger in cells with low BCOR as compared to controls. Both linsitinib and AEW541 suppressed colony formation in a dose-dependent manner in BCOR knockout or knockdown cells. Finally, high BCOR levels rendered retinoblastoma xenografts insensitive to linsitinib.
Conclusions: Loss of BCOR function is associated with more aggressive retinoblastoma cell line growth and chemoresistance, at least in part due to increased IGF1R signaling. Inhibiting IGF1R pharmacologically had a marked anti-tumor effect in aggressive retinoblastoma lacking BCOR, suggesting it as a new therapeutic target, although this still needs to be confirmed in clinical samples with BCOR mutations.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-04-16)
- 국외 연구진
- 의약학 > 종양의학
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