Screening in serum-derived medium reveals differential response to compounds targeting metabolism

Keene L Abbott; Ahmed Ali; Dominick Casalena; Brian T Do; Raphael Ferreira; Jaime H Cheah; Christian K Soule; Amy Deik; Tenzin Kunchok; Daniel R Schmidt; Steffen Renner; Sophie E Honeder; Michelle Wu; Sze Ham Chan; Tenzin Tseyang; Andrew T Stoltzfus; Sarah L J Michel; Daniel Greaves; Peggy P Hsu; Christopher W Ng; Chelsea J Zhang; Ali Farsidjani; Johnathan R Kent; Maria Lucia L Madariaga; Iva Monique T Gramatikov; Nicholas J Matheson; Caroline A Lewis; Clary B Clish; Matthew G Rees; Jennifer A Roth; Lesley Mathews Griner; Alexander Muir; Douglas S Auld; Matthew G Vander Heiden

doi:10.1016/j.chembiol.2023.08.007

Screening in serum-derived medium reveals differential response to compounds targeting metabolism

Cell Chem Biol. 2023 Sep 21;30(9):1156-1168.e7. doi: 10.1016/j.chembiol.2023.08.007. Epub 2023 Sep 8.

Authors

Keene L Abbott¹, Ahmed Ali², Dominick Casalena³, Brian T Do⁴, Raphael Ferreira⁵, Jaime H Cheah², Christian K Soule², Amy Deik⁶, Tenzin Kunchok⁷, Daniel R Schmidt⁸, Steffen Renner⁹, Sophie E Honeder¹⁰, Michelle Wu¹¹, Sze Ham Chan⁷, Tenzin Tseyang⁷, Andrew T Stoltzfus¹², Sarah L J Michel¹², Daniel Greaves¹³, Peggy P Hsu¹⁴, Christopher W Ng¹¹, Chelsea J Zhang¹⁵, Ali Farsidjani³, Johnathan R Kent¹⁶, Maria Lucia L Madariaga¹⁶, Iva Monique T Gramatikov⁸, Nicholas J Matheson¹⁷, Caroline A Lewis⁷, Clary B Clish⁶, Matthew G Rees⁶, Jennifer A Roth⁶, Lesley Mathews Griner³, Alexander Muir¹⁸, Douglas S Auld³, Matthew G Vander Heiden¹⁹

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology, Cambridge, MA 02139, USA.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.
⁸ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
⁹ Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland.
¹⁰ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
¹¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹² Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
¹³ Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02113, USA.
¹⁵ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁶ Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA.
¹⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁸ Ben May Department of Cancer Research, University of Chicago, Chicago, IL 60637, USA.
¹⁹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: mvh@mit.edu.

PMID: 37689063
PMCID: PMC10581593 (available on 2024-09-21)
DOI: 10.1016/j.chembiol.2023.08.007

Abstract

A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.

Keywords: Cancer cell metabolism; Culture media; Drug sensitivity; High-throughput screening; Nutrient environment; Phenotypic drug screening; Physiologic media.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Culture Techniques*
Cell Line
High-Throughput Screening Assays*
Humans
Small Molecule Libraries / pharmacology

Substances

Small Molecule Libraries

Abstract

Publication types

MeSH terms

Substances

Grants and funding