Crizotinib resistance overcome by ceritinib in an ALK-positive non-small cell lung cancer patient with brain metastases

Zhu, Zhouyu; Chai, Ying

doi:10.1097/md.0000000000008652

Cited by 8 publications

(2 citation statements)

References 8 publications

(10 reference statements)

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“…Notably, the concentration of 1 µM ceritinib that we used in long-term experiments can be achieved in the plasma of patients [22]. Lung cancer patients with brain metastases also respond to the treatment with ceritinib, suggesting that this drug is effective across the blood–brain barrier [29]. The concentration achieved in the mouse brain after oral administration was low, with a brain-to-plasma ratio below 0.3 [30], but the blood-to-brain exposure ratio of ceritinib in humans has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Vewinger

Huprich

Seidmann

et al. 2019

IJMS

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(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.

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Section: Discussionmentioning

confidence: 99%

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Vewinger

Huprich

Seidmann

et al. 2019

IJMS

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“…Ceritinib inhibits kinases such as ROS proto-oncogene 1 (ROS1), INSR, and IGF1R, although it is most active against ALK [9]. Lung cancer patients with brain metastases also respond to the treatment with ceritinib, suggesting that this drug is effective across the BBB [58]. The concentration achieved in the mouse brain after oral administration is low, with a brain-to-plasma ratio below 0.3 [59], but the blood-to-brain exposure ratio of ceritinib in humans is yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Ceritinib-Induced Regression of an Insulin-Like Growth Factor-Driven Neuroepithelial Brain Tumor

Russo

Paret

Alt

et al. 2019

IJMS

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The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.

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Crizotinib

2018

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Crizotinib resistance overcome by ceritinib in an ALK-positive non-small cell lung cancer patient with brain metastases

Cited by 8 publications

References 8 publications

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Ceritinib-Induced Regression of an Insulin-Like Growth Factor-Driven Neuroepithelial Brain Tumor

Crizotinib

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