Genomic sequencing and editing revealed the GRM8 signaling pathway as potential therapeutic targets of squamous cell lung cancer
2019
Abstract The study sought to explore novel genetic aberration driving
squamous cell lung carcinoma(LUSC). The whole
exome(WES), whole genome (WGS) and target region (TS) sequencings and
CRISPR-
Cas9
genome editingtechniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes ( FGFR2, GRM1,
PIK3CG, PIK3CA , ZFHX4 , CSMD3 , GRM8) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes ( CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through
CRISPR-
Cas9system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of
Metabotropic glutamate receptor 8(GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and
MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of
squamous cell lung cancercarrying GRM8 activating variants.
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