Open AccessFGFR2 loss sensitizes MYCN‐amplified neuroblastoma CHP134 cells to CHK1 inhibitor–induced apoptosis
Author(s) -
Ando Kiyohiro,
Ohira Miki,
Takada Ichiro,
CázaresOrdoñez Verna,
Suenaga Yusuke,
Nagase Hiroki,
Kobayashi Shinichi,
Koshinaga Tsugumichi,
Kamijo Takehiko,
Makishima Makoto,
Wada Satoshi
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15205
Subject(s) - neuroblastoma , cancer research , mapk/erk pathway , mek inhibitor , apoptosis , biology , kinase , cell cycle , microbiology and biotechnology , cell culture , genetics
Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. In this study, one CHK1i‐sensitive neuroblastoma cell line, CHP134, was investigated, which characteristically carries MYCN amplification and a chromosome deletion within the 10q region. Among several cancer‐related genes in the chromosome 10q region, mRNA expression of fibroblast growth factor receptor 2 ( FGFR2 ) was altered in CHP134 cells and associated with an unfavorable prognosis of patients with neuroblastoma. Induced expression of FGFR2 in CHP134 cells reactivated downstream MEK/ERK signaling and resulted in cells resistant to CHK1i‐mediated cell growth inhibition. Consistently, the MEK1/2 inhibitor, trametinib, potentiated CHK1 inhibitor–mediated cell death in these cells. These results suggested that FGFR2 loss might be prone to highly effective CHK1i treatment. In conclusion, extreme cellular dependency of ERK activation may imply a possible application for the MEK1/2 inhibitor, either as a single inhibitor or in combination with CHK1i in MYCN ‐amplified neuroblastomas.