Cancer Cell Line Genomics and Precision Medicine
Drugs targeted to DNA, DNA processing enzymes and chromatin are among the most widely used anticancer agents. Poly(ADPribose) polymerase (PARP) inhibitors have set a new paradigm by demonstrating that genomic evaluation of DNA repair pathways (inactivation of BRCA1, BRCA2, PALB2 and homologous recombination) defines patients who respond to those drugs. We will present our approaches to build on the value of cancer cell line genomic and pharmacological databases (NCI-60, Broad Institute CCLE, Mass General-Sanger CGP) to discover novel genomic determinants of response (exemplified by SLFN11 expression [Schlafen 11] and FANC [Fanconi anemia] inactivation) [1-3] and establish signatures of response to drugs targeted to DNA (temozolomide, platinum derivatives, nucleoside antimetabolites) and DNA enzymes (topoisomerase and PARP inhibitors) for improving precision medicine and precision therapeutics in oncology.
This is joint work with Vinodh Rajapakse, Augustin Luna, Margot Sunshine, Sudhir Varma and William Reinhold.
1. Murai J, Feng Y, Yu GK, Ru Y, Tang SW, Shen Y and Pommier Y. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget. 2016.
2. Sousa FG, Matuo R, Tang SW, Rajapakse VN, Luna A, Sander C, Varma S, Simon PH, Doroshow JH, Reinhold WC and Pommier Y. Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. DNA Repair (Amst). 2015; 28:107- 115.
3. Reinhold WC, Varma S, Sunshine M, Rajapakse V, Luna A, Kohn KW, Stevenson H, Wang Y, Heyn H, Nogales V, Moran S, Goldstein DJ, Doroshow JH, Meltzer PS, Esteller M and Pommier Y. The NCI-60 Methylome and Its Integration into CellMiner. Cancer Research. 2017; 77:601- 612.