TY - JOUR
T1 - Selective MET kinase inhibition in MET-dependent glioma models alters gene expression and induces tumor plasticity
AU - Van Den Heuvel, Corina N.A.M.
AU - Navis, Anna C.
AU - De Bitter, Tessa
AU - Amiri, Houshang
AU - Verrijp, Kiek
AU - Heerschap, Arend
AU - Rex, Karen
AU - Dussault, Isabelle
AU - Caenepeel, Sean
AU - Coxon, Angela
AU - Span, Paul N.
AU - Wesseling, Pieter
AU - Hendriks, Wiljan
AU - Leenders, William P.J.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/11
Y1 - 2017/11
N2 - The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/ VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distribution of the drug, we have now investigated the effects of the novel MET-selective inhibitor Compound A in the orthotopic E98 xenograft model. In vitro, Compound A proved a highly potent inhibitor of proliferation of MET-addicted cell lines. In line with its target selectivity, Compound A did not restore the leaky blood–brain barrier and was more effective than cabozantinib in inhibiting MET phosphorylation in vivo. Compound A treatment significantly prolonged survival of mice carrying E98 tumor xenografts, but did not prevent eventual progression. Contrasting in vitro results, the Compound A–treated xenografts displayed high levels of AKT phosphorylation despite the absence of phosphorylated MET. Profiling by RNA sequencing showed that in vivo transcriptomes differed significantly from those in control xenografts.
AB - The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/ VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distribution of the drug, we have now investigated the effects of the novel MET-selective inhibitor Compound A in the orthotopic E98 xenograft model. In vitro, Compound A proved a highly potent inhibitor of proliferation of MET-addicted cell lines. In line with its target selectivity, Compound A did not restore the leaky blood–brain barrier and was more effective than cabozantinib in inhibiting MET phosphorylation in vivo. Compound A treatment significantly prolonged survival of mice carrying E98 tumor xenografts, but did not prevent eventual progression. Contrasting in vitro results, the Compound A–treated xenografts displayed high levels of AKT phosphorylation despite the absence of phosphorylated MET. Profiling by RNA sequencing showed that in vivo transcriptomes differed significantly from those in control xenografts.
UR - http://www.scopus.com/inward/record.url?scp=85032832758&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0177
DO - 10.1158/1541-7786.MCR-17-0177
M3 - Article
C2 - 28751462
AN - SCOPUS:85032832758
SN - 1541-7786
VL - 15
SP - 1587
EP - 1597
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -