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Subtype and Pathway Specific Responses to Anticancer Compounds in Breast Cancer

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Subtype and Pathway Specific Responses to Anticancer Compounds in Breast Cancer Subtype and pathway specific responses to anticancer SPECIAL FEATURE compounds in breast cancer Laura M. Heisera,1, Anguraj Sadanandama,1,2, Wen-Lin Kuoa, Stephen C. Benzb, Theodore C. Goldsteinb, Sam Ngb, William J. Gibba, Nicholas J. Wanga,Safiyyah Ziyada, Frances Tongc, Nora Bayania, Zhi Hua, Jessica I. Billiga, Andrea Duereggera, Sophia Lewisa, Lakshmi Jakkulaa, James E. Korkolaa, Steffen Durincka, François Pepina, Yinghui Guana, Elizabeth Purdomc, Pierre Neuvialc,3, Henrik Bengtssonc,4, Kenneth W. Woodd, Peter G. Smithe, FEATURE Lyubomir T. Vassilevf, Bryan T. Hennessyg, Joel Greshockh, Kurtis E. Bachmanh, Mary Ann Hardwickeh, John W. Parki, Laurence J. Martonj, Denise M. Wolfa, Eric A. Collissoni, Richard M. Nevea, Gordon B. Millsg, Terence P. Speedc,k, BREAST CANCER SPECIAL Heidi S. Feilera, Richard F. Woosterh, David Hausslerb,l, Joshua M. Stuartb, Joe W. Graya,5,6, and Paul T. Spellmana,6,7 aLife Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; bDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 94720; cDepartment of Statistics, University of California, Berkeley, CA 94720; dCytokinetics, Inc., South San Francisco, CA 94080; eOncology, Millenium Pharmaceuticals, Cambridge, MA 02139; fHoffman-La Roche, Nutley, NJ 07110; gDepartment of Sytems Biology, MD Anderson Cancer Center, Houston, TX 77054; hGlaxoSmithKline, Collegeville, PA 19426; iDivision of Hematology-Oncology, University of California, San Francisco, CA 94143; jProgen Pharmaceuticals, Palo Alto, CA 94303; kBioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and lHoward Hughes Medical Institute, University of California, Santa Cruz, CA 95064 Edited by Kornelia Polyak, Dana-Farber Cancer Institute, Boston, MA, and accepted by the Editorial Board August 31, 2011 (received for review February 16, 2011) Breast cancers are comprised of molecularly distinct subtypes that amplified BCR-ABL (breakpoint cluster region - c-abl oncogene may respond differently to pathway-targeted therapies now 1, non-receptor tyrosine kinase) as sensitive to imatinib mesylate under development. Collections of breast cancer cell lines mirror (6). The Discovery Therapeutic Program of the National Cancer many of the molecular subtypes and pathways found in tumors, Institute (NCI) has pursued this approach on a large scale, iden- suggesting that treatment of cell lines with candidate therapeutic tifying associations between molecular features and responses to > ∼ compounds can guide identification of associations between 100,000 compounds in a collection of 60 cancer cell lines (7). molecular subtypes, pathways, and drug response. In a test of Although useful for detecting compounds with diverse responses, SYSTEMS BIOLOGY the NCI panel has limited power to detect subtype-specific re- 77 therapeutic compounds, nearly all drugs showed differential fi responses across these cell lines, and approximately one third sponses because of the relatively sparse representation of speci c cancers and subtypes thereof. We and others therefore have showed subtype-, pathway-, and/or genomic aberration-specific promoted the use of panels of well-characterized breast cancer responses. These observations suggest mechanisms of response cell lines for statistically robust identification of associations be- and resistance and may inform efforts to develop molecular assays tween in vitro therapeutic compound response and molecular that predict clinical response. subtypes and activated signaling pathways (4, 5). Here we report associations between quantitative proliferation measurements genomics | therapeutics | predictor enomic, epigenomic, transcriptional, and proteomic analyses Author contributions: L.M.H., A.S., D.M.W., E.A.C., G.B.M., T.P.S., R.F.W., D.H., J.M.S., J.W. Gof breast cancers reveal subtypes that may differ in pathway G., and P.T.S. designed research; L.M.H., A.S., W.-L.K., S.C.B., T.C.G., S.N., W.J.G., N.J.W., activity, progression, and response to therapy. In recognition of S.Z., F.T., N.B., Z.H., J.I.B., A.D., S.L., L.J., J.E.K., S.D., F.P., Y.G., E.P., P.N., H.B., B.T.H., E.A.C., these variances, more than 800 small molecule and biological R.M.N., H.S.F., and J.M.S. performed research; K.W.W., P.G.S., L.T.V., J.G., K.E.B., M.A.H., J.W.P., L.J.M., and R.F.W. contributed new reagents/analytic tools; S.D. and F.P. prepared inhibitors are now under development for the treatment of human and submitted data sets to the public repositories; and L.M.H., A.S., S.C.B., T.C.G., S.N., malignancies (1). These inhibitors vary in strength of subset and F.P., D.M.W., E.A.C., G.B.M., R.F.W., J.M.S., J.W.G., and P.T.S. wrote the paper. fi pathway speci city, with molecularly targeted experimental agents Conflict of interest statement: K.W.W. is an employee at Cytokinetics. P.G.S. is an employee tending toward stronger specificity (2). To test experimental at Millenium Pharmaceuticals. L.T.V. is an employee at Hoffman-LaRoche. J.G., K.E.B. M.A.H. agents more efficiently, sensitivity-enrichment schemes are needed and R.F.W., are employees and stockholders of GlaxoSmithKline. L.J.M. is an employee to identify potentially responsive patient subpopulations early at Progen. during clinical development. Responsive subsets can be identified This article is a PNAS Direct Submission. K.P. is a guest editor invited by the Editorial during the course of molecular marker-based clinical trials; how- Board. ever, this approach is expensive and does not allow early evalua- Data deposition: Genome data has been deposited at the European Genome-Phenome tion of experimental compounds in subpopulations most likely Archive (EGA), http://www.ebi.ac.uk/ega/,hostedattheEBI(accessionno. EGAS00000000059). Gene expression data for the cell lines were derived from Affymetrix to respond. As a consequence, the probability is high that com- GeneChip Human Gene 1.0 ST exon arrays. Raw data are available in ArrayExpress pounds that are very effective only in subpopulations of patients (E-MTAB-181). will be missed. An alternative approach is to identify candidate 1L.M.H. and A.S. contributed equally to this work. predictors of response by testing compounds in well-characterized 2 Present address: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute preclinical models so that early clinical trials can be powered to of Technology Lausanne, Lausanne, Switzerland. detect responding subpopulations predicted by these studies. This 3Present address: Laboratoire Statistique et Génome, Université d’Evry Val d’Essonne, approach would reduce development costs and increase the UMR CNRS 8071-USC INRA, 91 037 Evry, France. fi probability of nding drugs that may be particularly effective in 4Present address: Department of Epidemiology and Biostatistics, University of California, subsets of patients. San Francisco, CA 94143. Several studies support the utility of preclinical testing in cell- 5Present address: Department of Biomedical Engineering, Oregon Health and Sciences line panels for early and efficient identification of responsive University, Portland, OR 97239. molecular subtypes to guide early clinical trials. For example, 6To whom correspondence may be addressed. E-mail: [email protected] or SpellmaP@ cell-line panels predict lung cancers with EGFR mutations as OHSU.edu. fi responsive to ge tinib (3), breast cancers with human epidermal 7Present address: Department of Molecular and Medical Genetics, Oregon Health and growth factor receptor 2/erythroblastic leukemia viral oncogene Sciences University, Portland, OR 97239. HER2/ERBB2 fi homolog 2 ( ) ampli cation as responsive to tras- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tuzumab (4) and/or lapatinib (5), and tumors with mutated or 1073/pnas.1018854108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1018854108 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 and molecular features defining subtypes and activated pathways of gene-expression profiles for 49 breast cancer cell lines and five for 77 Food and Drug Administration-approved and investi- nonmalignant breast cell lines shows that the cell-line collection gational compounds in a panel of ∼50 breast cancer cell lines. models the luminal, basal, and claudin-low subtypes defined in Approximately one third show aberration or subtype specificity. primary tumor samples (SI Appendix, Fig. S1A) (8, 9). The basal We also show via integrative analysis of gene expression and and claudin-low subtypes map to the previously designated copy number data that some of the observed subtype-associated basal A and basal B subtypes, respectively (Dataset S1). A high- responses can be explained by specific pathway activities. The resolution SNP copy-number analysis (SI Appendix, Fig. S1B) quantitative response and cell-line characterizations are available confirms that the cell-line panel models regions of recurrent via the Stand Up to Cancer (SU2C)/University of California, amplification at 8q24 [v-myc myelocytomatosis viral oncogene Santa Cruz Cancer Genome Browser at https://genome-cancer. homolog (avian) (MYC)], 11q13 [cyclin D1 (CCND1)], 17q12 soe.ucsc.edu/. (ERBB2), 20q13 [serine/threonine kinase 15 (STK15)/aurora ki- nase A (AURKA)], and homozygous deletion at 9p21 [cyclin Results dependent kinase inhibitor 2A (CDKN2A)] that are found in Cell Lines Model Many Important Tumor Subtypes and Features. The primary tumors. Given
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