Genomic data from NSCLC tumors reveals correlation between SHP-2 activity and PD-L1 expression and suggests synergy in combining SHP-2 and PD-1/PD-L1 inhibitors.

Bing He,Keller J Toral,Esther P Black,Mark A Wuenschel

doi:10.1371/journal.pone.0256416

Abstract

The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC.

Highlights

Tumor genomic data informs benchtop experimental design anti-programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) therapies in non-small cell lung cancer (NSCLC)? We used this approach because we believe that the utilization of real-world datasets can inform and direct wet-lab experimentation
We present a quick and efficient process that, when combined with bench-side techniques, can offer substantial insight into the clinical translatability of commonly-used, highly-controlled model systems designed for drug discovery applications
A limitation of these data was that the reverse phase protein array (RPPA) data did not include expression levels of the unphosphorylated and inactive form of SHP-2 which would have been a useful control as informed by our wet-lab studies

Summary

Introduction

Lung cancers remain a leading cause of cancer morbidity and mortality worldwide despite increased efforts toward drug discovery and implementation of personalized medicine. Tumor genomic data informs benchtop experimental design. 1) for NCI-GDC, we used the "TCGA-LUAD" data set (the TCPA used the TCGA-LUAD-L4 subset); 2) for PMID: 30388455, GEO accession# GSE115978; 3) for PMID: 31959763, GEO accession# GSE136961; and 4) for PMID: 32015526, we used the full dataset

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