PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain

How PD-L1 expression is regulated in cancer is poorly understood.Here,we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers(CRCs).ERBB3 is one of the four members of the EGF receptor family,all with protein tyrosine kinase domains.ERBB3 is a pseudokinase with a high binding affin-ity to ATP.We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines.The ERBB3 ATP-binding mutant cells dramatically reduce IFN-g-induced PD-L1 expres-sion.Mechanistically,ERBB3 regulates IFN-g-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis.CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells.Knockin of a tumor-derived ERBB3 mutation located in the ki-nase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy,suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune check-point therapy.

Delivering on the promise of gene editing for cystic fibrosis

In this review,we describe a path for translation of gene editing into therapy for cystic fibrosis(CF).Cystic fibrosis results from mutations in the CFTR gene,with one allele predominant in patient populations.This simple,genetic etiology makes gene editing appealing for treatment of this disease.There already have been success in applying this approach to cystic fibrosis in cell and animal models,although these advances have been modest in comparison to advances for other disease.Less than six years after its first demonstration in animals,CRISPR/Cas gene editing is in early clinical trials for several disorders.Most clinical trials,thus far,attempt to edit genes in cells of the blood lineages.The advantage of the blood is that the stem cells are known,can be isolated,edited,selected,expanded,and returned to the body.The likely next trials will be in the liver,which is accessible to many delivery methods.For cystic fibrosis,the biggest hurdle is to deliver editors to other,less accessible organs.We outline a path by which delivery can be improved.The translation of new therapies doesn’t occur in isolation,and the development of gene editors is occurring as advances in gene therapy and small molecule therapeutics are being made.The advances made in gene therapy may help develop delivery vehicles for gene editing,although major improvements are needed.Conversely,the approval of effective small molecule therapies for many patients with cystic fibrosis will raise the bar for translation of gene editing.