Inactivating mutations of SMARCE1 promotes EGFR expression and suppress the responses to MET and ALK inhibitors in lung cancer

by Selleckchem | Feb 26 2015

The loss-of-function mutations in components of SWI/SNF chromatin-remodeling complexes are associated with the progression of multiple cancers and the resistance to some anti-tumor drugs. The findings indicates that SWI/SNF chromatin-remodeling complexes play key roles in regulating oncogenic signaling pathways as tumor suppressors. The study conducted by Papadakis et al. showed inactivating mutations in SMARCE1 gene, which encodes SWI/SNF subunit, upregulate EGFR expression and induce resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). The article was published in Cell Research.

Several studies have proved the tumor suppressor role of the SWI/SNF complexes, however, the molecular mechanisms of how do SWI/SNF components regulate malignant transformation, and how do they mediate oncogenic signaling are currently largely unknown. By using functional genetic screens, researchers examined genes that mediate drug responses to MET inhibition, and found a candidate gene, SMARCE1. This gene, also known as BAF57, encodes SWI/SNF component and its inactivation confers resistance to MET and ALK inhibitors by promoting EGFR expression in NSCLCS. Mechanically, SMARCE1 suppresses EGFR expression by binding to regulatory regains of gene locus ,and regulating expression of CBX2, a component of Polycomb Repressive Complex. In addition, the EGFR inhibitor gefitinib restores the sensitivity to MET and ALK inhibitors in SMARCE1-knowckdown cells with NSCLCs. The findings reveal the molecular mechanism in regulation of oncogenic signaling pathways by SMARCE1, indicating it as a potential target for therapeutic strategy against NSCLCs.

Reference:
Cell Res. 2015 Feb 6. doi: 10.1038/cr.2015.16.

Cat.No.	Product Name	Information
S1068	Crizotinib	Crizotinib is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively. It is also a potent ROS1 inhibitor with Ki value less than 0.025 nM. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.
S1108	TAE684 (NVP-TAE684)	TAE684 (NVP-TAE684) is a potent and selective ALK inhibitor which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM, 100-fold more sensitive for ALK than InsR. TAE684 (NVP-TAE684) induces cell cycle arrest and apoptosis.
S1025	Gefitinib	Gefitinib is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.
S7067	Tepotinib	Tepotinib is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. Tepotinib (EMD 1214063) induces autophagy. Phase 1.
S1070	PHA-665752	PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.
S7083	Ceritinib	Ceritinib is a potent inhibitor against ALK with IC50 of 0.2 nM in cell-free assays. Ceritinib (LDK378) also inhibits IGF-1R, InsR, STK22D and FLT3 with IC50 of 8 nM, 7 nM, 23 nM and 60 nM, respectively. Phase 3.