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Drug sensitivity in cancer cell lines is not tissue-specific.

Jaeger S, Duran-Frigola M, Aloy P - Mol. Cancer (2015)

Bottom Line: However, their clinical relevance remains controversial.We find that cancer-specific drugs do not show higher efficacies in cell lines representing the respective tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), c/Baldiri i Reixac 10-12, Barcelona, 08028, Catalonia, Spain. samira.jaeger@irbbarcelona.org.

ABSTRACT

Background: 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.

Findings: 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.

Conclusions: 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.

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Related in: MedlinePlus

Tissue specificity displayed by caner-specific drugs. (A) Sensitivity of cancer-specific drugs intended for breast cancer (41), colorectal cancer (24) and prostate cancer (38) across the NCI-60 panel covering 59 cancer cell lines derived from nine cancer tissues. The GI50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Each box represents the distribution of drug activities in a given cell line. Cell lines are organized in tissue slots. In red, we highlight the cell lines representing the intended tissue of the drugs. (B) Breast cancer subtype-specific analysis. Stratification of targeted agents according to the different breast cancer subtypes. Note that agents might be used for more than one subtype. (C) Sensitivity of HR-positive and triple negative breast cancer drugs with respect to subtype-specific breast cancer cell lines. Red indicates high drug activity while green indicates inactivity for a given cell line.
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Fig1: Tissue specificity displayed by caner-specific drugs. (A) Sensitivity of cancer-specific drugs intended for breast cancer (41), colorectal cancer (24) and prostate cancer (38) across the NCI-60 panel covering 59 cancer cell lines derived from nine cancer tissues. The GI50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Each box represents the distribution of drug activities in a given cell line. Cell lines are organized in tissue slots. In red, we highlight the cell lines representing the intended tissue of the drugs. (B) Breast cancer subtype-specific analysis. Stratification of targeted agents according to the different breast cancer subtypes. Note that agents might be used for more than one subtype. (C) Sensitivity of HR-positive and triple negative breast cancer drugs with respect to subtype-specific breast cancer cell lines. Red indicates high drug activity while green indicates inactivity for a given cell line.

Mentions: However, despite their fundamental role in biomedical research, the clinical relevance of cell lines remains highly controversial [6,7]. Apart from known technical and biological limitations, like contamination, missing tumor microenvironment, or lack of drug distribution and metabolism, the main concern is whether cancer cell lines are true representatives of primary tumors [8]. Prolonged culturing of immortalized cell lines may induce extensive modifications in their molecular characteristics, like secondary genomic changes [7,9], and it remains unclear how closely they still resemble the original tissue after undergoing a certain number of passages. To complement the ongoing debate from a pharmacological perspective, we analyzed the predictive power of cancer cell lines for elucidating cancer-specific drug responses. Considering the widely used NCI-60 panel [5], we assessed whether drugs for a particular cancer type display a higher efficacy in cell lines supposedly representing the respective cancer tissue. We focused on three cancer types, namely, breast, colorectal and prostate cancer, represented by five, seven and two cell lines, respectively, in the NCI-60. We analyzed all the 75 compounds, approved or experimental, associated with the treatment of these cancers that have also been tested in the NCI-60 (Additional file 1: Table S1 and Additional file 2: Table S2). We examined the sensitivity of each drug by considering its GI50 across the complete NCI-60 panel, derived from nine cancer tissues. The GI50, similar to IC50 and EC50, indicates the concentration required to inhibit cell proliferation by 50%, relative to untreated samples [5]. Note that we studied the activity of final drugs instead of the preliminary hit compounds expecting that the former remain active after preclinical optimization. FigureĀ 1A shows the sensitivity of the corresponding cancer cell lines towards cancer-specific agents (highlighted in red) in comparison to the sensitivity measured in cell lines representing other cancer tissues. Surprisingly, cancer-specific drugs do not show a significantly higher activity in cell lines representing the respective tissue (Wilcoxon test with Bonferroni correction for multiple testing; see Additional file 1). The same trend can be observed when focusing only on approved drugs or more specific targeted agents, and after normalizing drug sensitivity values across cell lines. To avoid biases caused by drugs with multiple therapeutic indications, we also analyzed more restrictive sets containing compounds exclusively associated with breast, colorectal or prostate cancers, obtaining equivalent outcomes (Additional file 1: Figures S1, S2 and S3). Overall, our results indicate that a simple selection of cell lines according to the tissue of interest does not reflect the eventual complexity in the clinics.Figure 1


Drug sensitivity in cancer cell lines is not tissue-specific.

Jaeger S, Duran-Frigola M, Aloy P - Mol. Cancer (2015)

Tissue specificity displayed by caner-specific drugs. (A) Sensitivity of cancer-specific drugs intended for breast cancer (41), colorectal cancer (24) and prostate cancer (38) across the NCI-60 panel covering 59 cancer cell lines derived from nine cancer tissues. The GI50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Each box represents the distribution of drug activities in a given cell line. Cell lines are organized in tissue slots. In red, we highlight the cell lines representing the intended tissue of the drugs. (B) Breast cancer subtype-specific analysis. Stratification of targeted agents according to the different breast cancer subtypes. Note that agents might be used for more than one subtype. (C) Sensitivity of HR-positive and triple negative breast cancer drugs with respect to subtype-specific breast cancer cell lines. Red indicates high drug activity while green indicates inactivity for a given cell line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359490&req=5

Fig1: Tissue specificity displayed by caner-specific drugs. (A) Sensitivity of cancer-specific drugs intended for breast cancer (41), colorectal cancer (24) and prostate cancer (38) across the NCI-60 panel covering 59 cancer cell lines derived from nine cancer tissues. The GI50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Each box represents the distribution of drug activities in a given cell line. Cell lines are organized in tissue slots. In red, we highlight the cell lines representing the intended tissue of the drugs. (B) Breast cancer subtype-specific analysis. Stratification of targeted agents according to the different breast cancer subtypes. Note that agents might be used for more than one subtype. (C) Sensitivity of HR-positive and triple negative breast cancer drugs with respect to subtype-specific breast cancer cell lines. Red indicates high drug activity while green indicates inactivity for a given cell line.
Mentions: However, despite their fundamental role in biomedical research, the clinical relevance of cell lines remains highly controversial [6,7]. Apart from known technical and biological limitations, like contamination, missing tumor microenvironment, or lack of drug distribution and metabolism, the main concern is whether cancer cell lines are true representatives of primary tumors [8]. Prolonged culturing of immortalized cell lines may induce extensive modifications in their molecular characteristics, like secondary genomic changes [7,9], and it remains unclear how closely they still resemble the original tissue after undergoing a certain number of passages. To complement the ongoing debate from a pharmacological perspective, we analyzed the predictive power of cancer cell lines for elucidating cancer-specific drug responses. Considering the widely used NCI-60 panel [5], we assessed whether drugs for a particular cancer type display a higher efficacy in cell lines supposedly representing the respective cancer tissue. We focused on three cancer types, namely, breast, colorectal and prostate cancer, represented by five, seven and two cell lines, respectively, in the NCI-60. We analyzed all the 75 compounds, approved or experimental, associated with the treatment of these cancers that have also been tested in the NCI-60 (Additional file 1: Table S1 and Additional file 2: Table S2). We examined the sensitivity of each drug by considering its GI50 across the complete NCI-60 panel, derived from nine cancer tissues. The GI50, similar to IC50 and EC50, indicates the concentration required to inhibit cell proliferation by 50%, relative to untreated samples [5]. Note that we studied the activity of final drugs instead of the preliminary hit compounds expecting that the former remain active after preclinical optimization. FigureĀ 1A shows the sensitivity of the corresponding cancer cell lines towards cancer-specific agents (highlighted in red) in comparison to the sensitivity measured in cell lines representing other cancer tissues. Surprisingly, cancer-specific drugs do not show a significantly higher activity in cell lines representing the respective tissue (Wilcoxon test with Bonferroni correction for multiple testing; see Additional file 1). The same trend can be observed when focusing only on approved drugs or more specific targeted agents, and after normalizing drug sensitivity values across cell lines. To avoid biases caused by drugs with multiple therapeutic indications, we also analyzed more restrictive sets containing compounds exclusively associated with breast, colorectal or prostate cancers, obtaining equivalent outcomes (Additional file 1: Figures S1, S2 and S3). Overall, our results indicate that a simple selection of cell lines according to the tissue of interest does not reflect the eventual complexity in the clinics.Figure 1

Bottom Line: However, their clinical relevance remains controversial.We find that cancer-specific drugs do not show higher efficacies in cell lines representing the respective tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), c/Baldiri i Reixac 10-12, Barcelona, 08028, Catalonia, Spain. samira.jaeger@irbbarcelona.org.

ABSTRACT

Background: 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.

Findings: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus