TY - JOUR
T1 - CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles
AU - Jain, P.
AU - Fierst, T. M.
AU - Han, H. J.
AU - Smith, T. E.
AU - Vakil, A.
AU - Storm, P. B.
AU - Resnick, A. C.
AU - Waanders, Angela Jae
N1 - Funding Information:
We thank Plexxikon Inc. for providing PLX4720 and PLX8394/PB-3 compounds and GlaxoSmithKline for providing trametinib. We greatly appreciate Jake Budlow, Tim Delaney, Namrata Choudhari and Katie Boucher for excellent technical assistance, and all members of the Resnick Lab for helpful discussion. We thank Dr Matthew Weitzman and Dr Mateusz P Koptyra for careful reading of the manuscript, and Dr Koptyra for helping with revision. This work was funded by the A Kids' Brain Tumor Cure Foundation Pediatric Low-Grade Astrocytoma Foundation (ACR), Voices Against Brain Cancer (ACR), the Children's Brain Tumor Foundation (ACR, AJW), the Damon-Runyon Sohn Pediatric Fellowship Award (AJW), a Hyundai Scholar Grant (AJW), the Bear Necessities Pediatric Cancer Foundation (AJW, ACR), the Rally Foundation for Childhood Cancer Research (AJW), Thea's Star of Hope (ACR, AJW), NIH National Center for Advancing Translational Sciences Award TL1TR000138 (HJH) and the National Institute of Health grant R01NS085336 (ACR).
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with â € paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.
AB - Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with â € paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.
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U2 - 10.1038/onc.2017.276
DO - 10.1038/onc.2017.276
M3 - Article
C2 - 28806393
AN - SCOPUS:85033446139
SN - 0950-9232
VL - 36
SP - 6348
EP - 6358
JO - Oncogene
JF - Oncogene
IS - 45
ER -
