Drug sensitivity in cancer cell lines is not tissue-specific
© Jaeger et al.; licensee BioMed Central. 2015
Received: 11 November 2014
Accepted: 29 January 2015
Published: 15 February 2015
Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating high-throughput screening of potential drugs. However, their clinical relevance remains controversial.
We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity. We find that cancer-specific drugs do not show higher efficacies in cell lines representing the respective tissues. Even when considering distinct cancer subtypes and targeted therapies, most drugs are evenly effective/ineffective throughout all cell lines.
To get the most out of cell line panels, it will be necessary to look into their molecular characteristics, and integrate them into systems biology frameworks.
Human cancer cell lines are widely used in vitro models for studying cancer and its biology . Apart from being valuable tools for identifying biomarkers and genetic variants that impact drug sensitivities [2,3], cancer cell lines play a pivotal role in the early stages of drug discovery, facilitating the screening of hundreds of potential drugs and their combinations before translating the outcomes into in vivo models and expensive clinical trials [4,5].
Given the intrinsic heterogeneity of most cancers , no individual cell line is likely to be a general representative for the distinct cancers derived from one tissue . Hence, we do not expect a tissue-specific drug to perform equally well across the corresponding cell lines. Breast cancer, for instance, is a heterogeneous disease with at least four recognized subtypes that require a specific treatment [12,13]. Most researchers select particular cell lines based on receptor status, common genetic mutations, molecular signatures, tumor type, as well as technical or methodological limitations for their experiments . Thus, mimicking this common approach, we considered the presence or absence of biomarkers that define the distinct breast cancer subtypes. Next we examined whether subtype-specific responses are reflected in cell lines representing distinct subtypes. The NCI-60 covers two subtypes, the triple-negative breast cancer (BT-549, HS-578 T and MDA-MB-231) and the HR-positive breast cancer subtype (MCF7 and T-47D). Neither the HER2-overexpressing nor the normal-like subtypes are included in the panel. Among the 25 targeted breast-cancer agents, 18 are indicated for HR-positive patients, 6 for triple-negative and 4 for HER2-overexpressing breast cancer (Figure 1B and Additional file 1: Table S3). According to this stratification, we assessed the sensitivity of the subtype-specific drugs in the corresponding cell lines. Figure 1C shows that the majority of drugs is equally active or inactive independent of the breast cancer subtype. Figitumumab, vandetanib, and gefitinib (I), for example, are evenly effective in HR-positive and triple-negative cell lines, while aromatase inhibitors like letrozole, anastrozole and aminoglutethimide are basically inactive and would not have been discovered through screening cell lines from this panel. Only four out of 18 HR-positive drugs, i.e., PD-332991, raloxifene, tamoxifen (I), and fulvestrant, exhibit a higher specificity in at least one of the HR-positive cell lines. Conversely, midostaurin, a targeted drug against HR-positive tumors, only shows activity in triple-negative cell lines. As the NCI-60 only involves five breast cancer cell lines, which only partially reflect the distinct subtypes, we performed the same analysis on the more comprehensive Cancer Cell Line Encyclopedia (CCLE) . Considering 30 breast cancer cell lines and 14 targeted agents, both stratified into subtypes, we still observe a largely varying compound sensitivity rather than subtype-specific responses in the corresponding cell lines (Additional file 1: Figure S4). Thus, even when accounting for subtype-specific differences in the NCI-60, or considering a much larger cell line panel with a broader representation of breast cancer subtypes  (see Additional file 1: Figure S4), the previously observed tendencies regarding tissue specificity still hold.
Similarly, we investigated whether intended drug targets are expressed in the corresponding cell lines and, if so, whether the drug is active in this cell line, exploiting proteomics data of NCI-60 . Again, we could not correlate target expression with drug sensitivity (Additional file 1: Figure S5). One of the few exceptions is presented by the set of EGFR modulators, Gefitinib and Erlotinib, to which cell lines are indeed more sensitive when EGFR is expressed. Yet, in the majority of instances drug activity does not depend on the presence or absence of the intended targets, which indicates that several factors, beyond target expression, determine drug sensitivity.
Although alternative models for drug screening and development are generated , cancer cell lines have been and will be an essential component of cancer research and drug discovery . However, as we observed, relying on assays performed in a few selected cell lines may result in incorrect or misleading conclusion, and thus is unlikely to predict clinical outcomes. Cell line panels, on the other hand, may embrace the underlying complexity and variability of cancer. Yet, to fully exploit their invaluable potential, we have to move beyond ‘one marker, one cell line’ studies and incorporate the large amount of molecular (‘omics’) profiles into robust systems biology frameworks [15,16,18-20]. We believe that identifying and combining the key features that each cell line is able to reproduce, beyond tissue and subtype specificity, will bring screening panels at the forefront of a more successful drug discovery.
We would like to thank all the IRB Barcelona PIs, specially E. Giralt and A.R. Nebreda, R. Mosca and the Biostatistics Unit for helpful discussions. This work was partially supported by the European commission through the SyStemAge project (Agreement no: 306240) and the European Research Council through the SysPharmAD grant (Agreement no: 201014). MDF is a recipient of the Spanish FPU Fellowship.
- Weinstein JN. Drug discovery: cell lines battle cancer. Nature. 2012;483:544–5.View ArticlePubMedGoogle Scholar
- Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.View ArticlePubMed CentralPubMedGoogle Scholar
- Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.View ArticlePubMedGoogle Scholar
- Gazdar AF, Girard L, Lockwood WW, Lam WL, Minna JD. Lung cancer cell lines as tools for biomedical discovery and research. J Natl Cancer Inst. 2010;102:1310–21.View ArticlePubMed CentralPubMedGoogle Scholar
- Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6:813–23.View ArticlePubMedGoogle Scholar
- Gazdar AF, Gao B, Minna JD. Lung cancer cell lines: useless artifacts or invaluable tools for medical science? Lung Cancer. 2010;68:309–18.View ArticlePubMed CentralPubMedGoogle Scholar
- Gillet JP, Varma S, Gottesman MM. The clinical relevance of cancer cell lines. J Natl Cancer Inst. 2013;105:452–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.View ArticlePubMed CentralPubMedGoogle Scholar
- Wilding JL, Bodmer WF. Cancer cell lines for drug discovery and development. Cancer Res. 2014;74:2377–84.View ArticlePubMedGoogle Scholar
- Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 1805;2010:105–17.Google Scholar
- Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7:659–72.View ArticlePubMedGoogle Scholar
- Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.View ArticlePubMedGoogle Scholar
- van ’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.View ArticlePubMedGoogle Scholar
- Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011;13:215.View ArticlePubMed CentralPubMedGoogle Scholar
- Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Moghaddas Gholami A, Hahne H, Wu Z, Auer FJ, Meng C, Wilhelm M, et al. Global proteome analysis of the NCI-60 cell line panel. Cell Rep. 2013;4:609–20.View ArticlePubMedGoogle Scholar
- Ferreira D, Adega F, Chaves R. The Importance of Cancer Cell lines as in vitro Models in Cancer Methylome Analysis and Anticancer Drugs Testing. In: Lopez-Camarillo C, Arechaga-Ocampo E, editors. Oncogenomics and Cancer Proteomics - Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer. InTech. 2013.Google Scholar
- Abaan OD, Polley EC, Davis SR, Zhu YJ, Bilke S, Walker RL, et al. The exomes of the NCI-60 panel: a genomic resource for cancer biology and systems pharmacology. Cancer Res. 2013;73:4372–82.View ArticlePubMedGoogle Scholar
- Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, et al. Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet. 2000;24:227–35.View ArticlePubMedGoogle Scholar
- Dancik GM, Ru Y, Owens CR, Theodorescu D. A framework to select clinically relevant cancer cell lines for investigation by establishing their molecular similarity with primary human cancers. Cancer Res. 2011;71:7398–409.View ArticlePubMed CentralPubMedGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.