Copy Number Alterations in Tumor Genomes Deleting Antineoplastic Drug Targets Partially Compensated by Complementary Amplifications.

Ha Vu Tran, Alexandra K Kiemer, Volkhard Helms

Journal: Cancer genomics & proteomics 2018;15(5):365-378

PMID: 30194077

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Abstract

BACKGROUND/AIM

Genomic DNA copy number alterations (CNAs) are frequent in tumors and have been catalogued by The Cancer Genome Atlas project. Emergence of chemoresistance frequently renders drug therapies ineffective.

MATERIALS AND METHODS

We analyzed how CNAs recurrently found in the genomes of TCGA patients of thirty-one tumor types affect protein targets of antineoplastic (AN) agents.

RESULTS

CNA deletions more frequently affected the targets of AN agents than CNA amplifications. Interestingly, in seven tumors we observed signs of compensatory CNAs. For example, in glioblastoma multiforme, two target genes (FLT1, FLT3) of the experimental drug sorafenib were recurrently deleted, whereas another target (KDR) of sorafenib was recurrently amplified. In renal clear cell carcinoma, the target FLT1 of pazopanib, sunitinib, sorafenib, and axitinib was recurrently deleted, whereas FLT4 bound by the same drugs, was recurrently amplified.

CONCLUSION

Deletions of AN target proteins can be compensated by amplification of alternative targets.

Address: Saarland University, Center for Bioinformatics, Saarbruecken, Germany.; Department of Computer Science, Faculty of Information Technology, Vietnam National University of Agriculture, Hanoi, Vietnam.; Saarland University, Department of Pharmacy, Pharmaceutical Biology, Saarbruecken, Germany.; Saarland University, Center for Bioinformatics, Saarbruecken, Germany [email protected].

DOI: 10.21873/cgp.20095

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MeSH Terms: Antineoplastic Agents, Axitinib, Carcinoma, Renal Cell, DNA Copy Number Variations, Drug Resistance, Neoplasm, Female, Genome, Human, Glioblastoma, Humans, Imidazoles, Indazoles, Indoles, Male, Molecular Targeted Therapy, Niacinamide, Phenylurea Compounds, Pyrroles, Sorafenib, Sunitinib, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-3, fms-Like Tyrosine Kinase 3