FGFR2 loss sensitizes MYCN‐amplified neuroblastoma CHP134 cells to CHK1 inhibitor–induced apoptosis

Ando, Kiyohiro; Ohira, Miki; Takada, Ichiro; Cázares-Ordoñez, Verna; Suenaga, Yusuke; Nagase, Hiroki; Kobayashi, Shinichi; Koshinaga, Tsugumichi; Makishima, Makoto; Wada, Satoshi

doi:10.1111/cas.15205

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…Tgfb1 , Tgfbr3 , Ephb3 , and Ephb4 ), which is interesting as previous research has shown that cross-talk between TGF-β and Ephrin pathways interferes with Schwann cell differentiation to drive peripheral nerve regeneration 31 . Additionally, we detected hypermethylation in Fgfr2 , which is intriguing as inhibiting Fgfr2 has shown promise in sensitizing MYCN -amplified NB to CHK1 inhibitors 32 . Hypomethylated regions were less frequent but still present following ATRi treatment (Fig.…”

Section: Resultsmentioning

confidence: 72%

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ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Borenäs,

Umapathy,

Lind

et al. 2023

Preprint

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High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

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Section: Resultsmentioning

confidence: 72%

“…Additionally, we detected hypermethylation in Fgfr2, which is intriguing as inhibiting Fgfr2 has shown promise in sensitizing MYCN-amplified NB to CHK1 inhibitors 32 . Hypomethylated regions were less frequent but still present following ATRi treatment (Fig.…”

Section: Tumours Treated With Elimusertib Exhibit Differential Dna Me...mentioning

confidence: 72%

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Borenäs,

Umapathy,

Lind

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Among interesting loci hypermethylated in response to ATRi, we noted components of the TGF-beta signaling and Ephrin pathways (e.g., Tgfb1 , Tgfbr3 , Ephb3 , and Ephb4 ), interesting as cross-talk between TGF-β and Ephrin pathways interferes with Schwann cell differentiation to drive peripheral nerve regeneration ( 34 ). Additionally, we detected hypermethylation in Fgfr2 , which is intriguing as inhibiting Fgfr2 has shown promise in sensitizing MYCN -amplified NB to CHK1 inhibitors ( 35 ). Hypomethylated regions were less frequent but still present following ATRi treatment ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 78%

ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Borenäs,

Umapathy,

Lind

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

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“… 3 This was also supported by previous reports that showed that inhibition of FGFR2-mediated signaling induced apoptosis in several cancer cells. 68 – 70 The FGFR2cKO mice also showed increased apoptotic loss of keratocytes at the region exhibiting localized corneal thinning compared to control mice ( Fig. 7 ).…”

Section: Discussionmentioning

confidence: 88%

Role of Fibroblast Growth Factor Receptor 2 (FGFR2) in Corneal Stromal Thinning

Joseph,

Boateng,

Srivastava

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose To determine the role of fibroblast growth factor receptor 2 (FGFR2)–mediated signaling in keratocytes during corneal development, a keratocyte-specific FGFR2-knockout (named FGFR2cKO ) mouse model was generated, and its phenotypic characteristics were determined. Methods A FGFR2cKO mouse model was generated by the following method: FGFR2 flox mice were crossed with the inducible keratocyte specific-Cre mice (Kera-rtTA/tet-O-Cre). Both male and female FGFR2cKO- and control mice (1 to 3-months-old) were analyzed for changes in corneal topography and pachymetry maps using the optical coherence tomography (OCT) method. The comparative TUNEL assay and immunohistochemical analyses were performed using corneas of FGFR2cKO and control mice to determine apoptotic cells, and expression of collagen-1 and fibronectin. Transmission electron microscopic analysis was conducted to determine collagen structures and their diameters in corneas of FGFR2cKO and control mice. Results OCT-analyses of corneas of FGFR2cKO mice (n = 24) showed localized central thinning and an increased corneal steepness compared to control mice (n = 23). FGFR2cKO mice further showed a decreased expression in collagen-1, decreased collagen diameters, acute corneal hydrops, an increased fibronectin expression, and an increased number of TUNEL-positive cells suggesting altered collagen structures and keratocytes’ apoptosis in the corneas of FGFR2cKO mice compared to control mice. Conclusions The FGFR2cKO mice showed several corneal phenotypes (as described above in the results) that are also exhibited by the human keratoconus corneas. The results suggested that the FGFR2cKO mouse model serves to elucidate not only the yet unknown role of FGFR2-mediated signaling in corneal physiology but also serves as a model to determine molecular mechanism of human keratoconus development.

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FGFR2 loss sensitizes MYCN‐amplified neuroblastoma CHP134 cells to CHK1 inhibitor–induced apoptosis

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 8 publications

References 46 publications

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Role of Fibroblast Growth Factor Receptor 2 (FGFR2) in Corneal Stromal Thinning

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