Unknown

Dataset Information

0

Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors.


ABSTRACT: Despite the development of potent RAF/mitogen-activated protein kinase (MAPK) pathway inhibitors, only a fraction of BRAF-mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6) secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term "oncogene mimicry." This model may guide future strategies for overcoming primary resistance observed in these tumors.

SUBMITTER: Sos ML 

PROVIDER: S-EPMC4294625 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

Similar Datasets

2012-01-01 | S-EPMC3308191 | BioStudies
2015-01-01 | S-EPMC4390490 | BioStudies
2016-01-01 | S-EPMC5127364 | BioStudies
1000-01-01 | S-EPMC4674359 | BioStudies
2019-01-01 | S-EPMC6770736 | BioStudies
2013-01-01 | S-EPMC3606893 | BioStudies
2019-01-01 | S-EPMC6733264 | BioStudies
2015-01-01 | S-EPMC4894664 | BioStudies
2010-01-01 | S-EPMC2930420 | BioStudies
2018-01-01 | S-EPMC5915992 | BioStudies