Table 1.
Leading Edge Enrichment Analysis
| Enrichments: ↑ IPF, ↓ Saracatinib |
Enrichments: ↓ IPF, ↑ Saracatinib |
|||||||
|---|---|---|---|---|---|---|---|---|
| Library | Gene Set | FDR | Genes in Overlap | Fold Change | Gene Set | FDR | Genes in Overlap | Fold Change |
| Hallmark | IFNγ response | 1.79 × 10−12 | ADAR, CD74, HLA-A, HLA-B, HLA-DMA, HLA-G, ICAM1, IFI30, IFIT3, IFITM3, IRF1, LGALS3BP, LY6E, MT2A, MX1, MYD88, NFKBIA, PTPN6, SERPING1 | 9.48 | Myc targets | 3.47 × 10−9 | CCT2, DEK, DHX15, ERH, GLO1, HNRNPA1, IARS, LDHA, NPM1, PSMA6, RPL6, RPLP0, SLC25A3, YWHAQ | 9.28 |
| EMT | 5.94 × 10−11 | CAPG, COL1A1, COL4A2, COL6A2, CYR61, FLNA, FN1, GEM, HTRA1, ID2, IGFBP2, IGFBP4, SERPINE1, SERPINH1, TAGLN, TGFBI, VIM | 8.54 | Allograft rejection | 1.35 × 10−4 | B2M, HIF1A, IFNGR1, MRPL3, NPM1, RPS3A, TIMP1 | 8.59 | |
| TNF-α signaling via NF-κB | 4.03 × 10−10 | CCND1, CD83, CYR61, EGR1, FOSB, GEM, ICAM1, ID2, IER2, IRF1, JUNB, KDM6B, LAMB3, LIF, NFKBIA, SERPINE1, SLC2A3, ZFP36 | 7.88 | Apoptosis | 4.39 × 10−4 | CAV1, GPX3, IFNGR1, PPT1, TGFBR3, TIMP1, TXNIP | 6.91 | |
| Complement | 2.50 × 10−8 | APOC1, C3, COL4A2, CSRP1, CTSD, CTSH, DUSP6, FN1, GNAI2, GNB2, IRF1, PFN1, SERPINE1, SERPING1, TIMP2 | 7.81 | Inflammatory response | 1.49 × 10−2 | ADM, HIF1A, LAMP3, NAMPT, TIMP1 | 6.08 | |
| Coagulation | 3.70 × 10−8 | APOC1, C3, CRIP2, CSRP1, CTSH, DUSP6, FN1, GNB2, HTRA1, SERPINE1, SERPING1, USP11 | 10.07 | Reactive oxygen species | 1.81 × 10−2 | GPX3, PRDX1, PRDX6 | 8.95 | |
| IFNα response | 1.61 × 10−6 | ADAR, CD74, HLA-C, IFI30, IFIT3, IFITM3, IRF1, LGALS3BP, LY6E, MX1 | 9.03 | Oxidative phosphorylation | 1.84 × 10−2 | COX6C, COX7A2, LDHA, NDUFA4, SLC25A3, SLC25A5 | 3.98 | |
| Allograft rejection | 2.79 × 10−5 | CAPG, CD74, FLNA, HLA-A, HLA-DMA, HLA-E, HLA-G, ICAM1, LIF, PTPN6 | 6.67 | Androgen response | 3.27 × 10−2 | B2M, MYL12A, SGK1, SLC38A2 | 5.77 | |
| Apical junction | 4.75 × 10−5 | ACTB, ACTG1, ACTN4, CAP1, EVL, GNAI2, ICAM1, LAMB3, PFN1, TGFBI, VASP, ZYX | 5.63 | EMT | 4.94 × 10−2 | CD59, GJA1, TGFBR3, TIMP1 | 3.70 | |
| KEA | RIPK3 | 3.42 × 10−6 | ACTB, ACTG1, ACTN4, FLNA, GNB2, HSPA8, RPS27, AUB52, UBB, VIM | 8.31 | MAP3K14 | 3.89 × 10−10 | HNRNPA1, HSPA1A, IARS, NPM1, RPL24, RPL4, RPL6, RPL7A, RPL10, RPS11, RPS23, RPS3A, RPS7 | 12.74 |
| MAP3K3 | 5.42 × 10−6 | ACTB, ACTG1, ACTN4, FLNA, GNAI2, GNB2, HSPA8, NFKBIA, RPS27, TUBA1C, UBA52, UBB, VIM | 5.66 | RIPK3 | 3.42 × 10−6 | CCt2, HNRNPA1, HSPA1A, PPP1CB, PPP1CC, PRDX1, SLC25A3, SLC25A5 | 12.17 | |
| MAP3K1 | 1.56 × 10−5 | ACTB, ACTG1, FLNA, HSPA8, LGALS3BP, NFKBIA, RPL35, RPS27, UBA52, UBB, VIM | 6.52 | MAP3K1 | 1.71 × 10−3 | HSPA1A, RPL24, RPL4, RPS11, RPS23, SLC25A5 | 6.50 | |
| MAP3K14 | 4.89 × 10−4 | ACTB, ACTG1, FAU, HSPA8, NFKBIA, RPL35, RPS10, RPS18, RPS20 | 4.82 | MAP3K3 | 7.38 × 10−3 | CCT2, HSPA1A, IARS, PPP1CC, SLC25A5, YWHAQ | 4.79 | |
Definition of abbreviations: EMT = epithelial–mesenchymal transition; IPF = idiopathic pulmonary fibrosis; KEA = kinase enrichment analysis; MAP = mitogen-activated protein; NF-κB = nuclear factor-κB; RIPK3 = receptor-interacting serine/threonine-protein kinase 3; TNF = tumor necrosis factor.
Enrichment analysis was performed on the leading edge of saracatinib drug signature versus IPF disease signature (GSE24206). The drug–disease pair that showed the highest connectivity was used for the analysis, namely “Saracatinib MCF7 Low Dose” versus “Advanced_IPF_explant_upper_lobe obtained from GSE24206”. The fold change reflects the results from a Fisher exact test, which assesses the overlap in gene sets that inversely perturbed between IPF and saracatinib (genes that are both downregulated in IPF and upregulated by saracatinib) and informative gene sets. Gene sets and overlapping genes are listed.