Dataset Information

Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.

ABSTRACT: Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.

SUBMITTER: Zhao W

PROVIDER: S-EPMC7738392 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.

Zhao Wei W Li Jun J Chen Mei-Ju M MM Luo Yikai Y Ju Zhenlin Z Nesser Nicole K NK Johnson-Camacho Katie K Boniface Christopher T CT Lawrence Yancey Y Pande Nupur T NT Davies Michael A MA Herlyn Meenhard M Muranen Taru T Zervantonakis Ioannis K IK von Euw Erika E Schultz Andre A Kumar Shwetha V SV Korkut Anil A Spellman Paul T PT Akbani Rehan R Slamon Dennis J DJ Gray Joe W JW Brugge Joan S JS Lu Yiling Y Mills Gordon B GB Liang Han H

Cancer cell 20201105 6

Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that int ...[more]

PMID: 33157050

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Project description:Steroid hormones regulate a variety of physiological processes, including reproductive function, and are widely used in hormonal therapy. Synthetic progestogens, or progestins, were designed to mimic progesterone (P4) for use in contraception and hormonal replacement therapy in women. Medroxyprogesterone acetate (MPA) and norethisterone (NET) are the most widely used injectable contraceptives in the developing world, while other progestins such as levonorgestrel (LNG), etonogestrel (ETG) and nestorone (NES) are used in or being developed for other forms of contraception. As concerns remain about the most appropriate choice of progestin and dosage, and the associated side-effects, the mechanisms and biological effects of progestins are frequently investigated in various in vitro mammalian cell line and tissue models. However, whether progestogens are differentially metabolised in different cell types in vivo or in vitro is unknown. For nine mammalian cell lines commonly used to investigate progestogen mechanisms of action, we developed and validated an ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) protocol for simultaneously quantifying the metabolism of the above-mentioned steroids. We show for the first time that, while 50-100% of P4 was metabolised within 24 h in all cell lines, the metabolism of the progestins is progestin- and cell line-specific. We also show that MPA and NET are significantly metabolised in human cervical tissue, but to a lesser extent than P4. Taken together, our findings suggest that differential progestogen metabolism may play a role in cell-specific therapeutic and side-effects. Relative affinities for binding to steroid receptors as well as potencies, efficacies and biocharacters for transcriptional activity of progestins, relative to P4, are most frequently determined using some of the cell lines investigated. Our results, however, suggest that differential metabolism of progestins and P4 may confound these results. In particular, metabolism may under-estimate the receptor-mediated intrinsic in vitro binding and dose-response values and predicted endogenous physiological effects of P4.

Dataset Information

Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.

Publications

Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines.

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