In the tumor recurrence 22. 2% of the tumor showed a com plete LOH signal, up from 5. 1% in the original tumor. The previous observed pat tern of focal amplification and loss of 18q in the initial tumor was recapitulated in the tumor recurrence, indi cating that this specific pattern was reproducible between samples and not likely due to selleck chem Crenolanib heterogeneity in the original tumor sample. There were Inhibitors,Modulators,Libraries 459 differentially expressed Inhibitors,Modulators,Libraries genes in the metastatic skin nodule versus the blood compendium. Of these, 209 overlapped with the differentially expressed genes in the lung tumor versus blood compendium set. In the skin metastasis relative to lung there were 6,440 differentially expressed genes. The 23 amplified, over expressed or mutated genes in cancer pathways targeta ble by approved drugs are listed in Table S3 in Addi tional file 1.
The cancer recurrence exhibited strong up regulation of transcripts Inhibitors,Modulators,Libraries from genes in both the MAPK ERK and PI3K AKT pathways. There are striking increases in expression of the receptor tyrosine kinases B and their growth factor ligands, neurturin. Other genes within these pathways, such as AKT1, MEK1 and PDGFA, also appear amplified in copy number in the skin tumor compared to the lung tumor. Sunitinib resistance has been observed to be mediated by IL8 in renal cell carcinoma. This is reflected in the tumor data, where IL8 became highly over expressed in the cancer recurrence. Pathway analysis also shows IL8 signaling to be significant in the suniti nib resistant skin tumor compared to the lung tumor.
Though the mechanism Inhibitors,Modulators,Libraries of resistance is still unclear, IL8 has been observed to transactivate Inhibitors,Modulators,Libraries EGFR and downstream ERK, stimulating cell proliferation in cancer cells. Taken together, these data suggest that the mechanisms of resistance to the RET targeting selective kinase inhibitors sunitinib and sorafenib are the up regulation of the targeted MAPK ERK pathway and the parallel PI3K AKT path way. We speculate that perhaps www.selleckchem.com/products/VX-770.html only a cocktail of tar geted drugs would be able to mitigate the proliferation of the tumor cells. Conclusions High throughput sequencing of the patients tumor and normal DNA provided a comprehensive determination of copy number alterations, gene expression levels and protein coding mutations in the tumor. Correlation of the up regulated and amplified gene products with known cancer related pathways provided a putative mechanism of oncogenesis that was validated through the successful administration of targeted therapeutic compounds. In this case, known targets of sunitinib and sorafenib were up regulated, implying that the tumor would be sensitive to this drug. Sequence analysis of the protein coding regions was also able to determine that the drug binding sites for sunitinib were intact.