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.
Digital Object Identifier (DOI)
All data used in this study were accessed from 3 published studies and publicly-available RNA sequencing data from NCI-GDC. Specifically, 1) for NCI-GDC, we used the "TCGA-LUAD" data set (similarly, 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.
Toral, Keller J.; Wuenschel, Mark A.; and Black, Esther P., "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" (2021). Pharmaceutical Sciences Faculty Publications. 171.
S1 Fig. SHP2_pY542 significantly correlates with phosphorylated proteins found in pathways that are SHP-2 targets. https://doi.org/10.1371/journal.pone.0256416.s001
journal.pone.0256416.s002.tif (294 kB)
S2 Fig. KRAS mutation status had no impact on PTPN11 and CD274 relationship. https://doi.org/10.1371/journal.pone.0256416.s002
journal.pone.0256416.s003.tif (391 kB)
S3 Fig. Outlier analysis of PTPN11 TPM values for NSCLC response study. https://doi.org/10.1371/journal.pone.0256416.s003