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      Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs

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          Abstract

          Drug sensitivity and resistance are conventionally quantified by IC 50 or E max values, but these metrics are highly sensitive to the number of divisions taking place over the course of a response assay. The dependency of IC 50 and E max on division rate creates artefactual correlations between genotype and drug sensitivity while obscuring valuable biological insights and interfering with biomarker discovery. We derive alternative drug response metrics that are insensitive to division number. These are based on estimating the magnitude of drug-induced growth rate inhibition (GR) using endpoint or time-course assays. We show that GR 50 and GR max are superior to conventional metrics for assessing the effects of drugs in dividing cells. Moreover, adopting GR metrics requires only modest changes in experimental protocols. We expect GR metrics to improve the study of cell signaling and growth using drugs, discovery of drug response biomarkers, and identification of drugs effective on specific patient-derived tumor cells.

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          Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

          M. Serrano, A. Lin, M. McCurrach … (1997)
          Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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            Breast cancer molecular subtypes respond differently to preoperative chemotherapy.

            Roman Rouzier, Charles Perou, W Symmans … (2005)
            Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported "breast intrinsic" gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor-negative subtypes. The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.
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              Correlating chemical sensitivity and basal gene expression reveals mechanism of action

              Matthew G. Rees, Brinton Seashore-Ludlow, Jaime H. Cheah … (2016)
              Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ~19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters, and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101215604
                Journal ID (pubmed-jr-id): 32338
                Journal ID (nlm-ta): Nat Methods
                Journal ID (iso-abbrev): Nat. Methods
                Title: Nature methods
                ISSN (Print): 1548-7091
                ISSN (Electronic): 1548-7105
                Publication date Nihms-submitted: 25 April 2016
                Publication date (Electronic): 02 May 2016
                Publication date (Print): June 2016
                Publication date PMC-release: 02 November 2016
                Volume: 13
                Issue: 6
                Pages: 521-527
                Affiliations
                [1 ]HMS LINCS Center, Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, USA
                Author notes
                [* ]Corresponding author: Peter K. Sorger, 200 Longwood Avenue, Boston, MA 02115, peter_sorger@ 123456hms.harvard.edu , phone (617) 432-6902, fax (617) 432-6990
                [2]

                These authors contributed equally

                Article
                Manuscript ID: NIHMS775875
                DOI: 10.1038/nmeth.3853
                PMC ID: 4887336
                PubMed ID: 27135972
                SO-VID: 61dbc9bb-f601-41d0-a517-2c73b623e6a8
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Categories
                Subject: Article

                ScienceOpen disciplines: Life sciences
                Keywords: ic50,drug sensitivity and resistance,pharmacology,biomarkers,cell cycle
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: ic50, drug sensitivity and resistance, pharmacology, biomarkers, cell cycle

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