TY - JOUR
T1 - Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance
AU - Javidi-Sharifi, Nathalie
AU - Traer, Elie
AU - Martinez, Jacqueline
AU - Gupta, Anu
AU - Taguchi, Takehiro
AU - Dunlap, Jennifer
AU - Heinrich, Michael C.
AU - Corless, Christopher L.
AU - Rubin, Brian P.
AU - Druker, Brian J.
AU - Tyner, Jeffrey W.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinibresistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinibresistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinibresistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinibnaïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib.
AB - Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinibresistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinibresistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinibresistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinibnaïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib.
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U2 - 10.1158/0008-5472.CAN-14-0573
DO - 10.1158/0008-5472.CAN-14-0573
M3 - Article
C2 - 25432174
AN - SCOPUS:84928803593
SN - 0008-5472
VL - 75
SP - 880
EP - 891
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -