Abstract
Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug-response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, additive compound pairs with distinct growth/death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.
Highlights
Quantifying cellular response to therapeutic compounds is essential to understanding their mechanisms of action and assessing therapeutic efficacy[1,2,3]
Viability alone is insufficient to distinguish cell growth and death effects To test whether growth and death are confounded in livecell measurements, we first explored the uncertainty in a model using only these measurements (Fig. 1a)
Two major phenotypic changes we can observe as cellular responses to drugs are cell growth and death
Summary
Quantifying cellular response to therapeutic compounds is essential to understanding their mechanisms of action and assessing therapeutic efficacy[1,2,3]. In the case of cancer treatments, and often with other diseases, drug activities are evaluated by quantifying the number of live cells after a short period using direct or surrogate measurements[4,5]. Quantities beyond the number and viability of cells provide valuable information about the cellular response. Along with altering cell proliferation, promoting cell death is another important index of drug efficacy[6,7]. Incomplete eradication of drug-susceptible malignant cells allows the survival of drug-tolerant persister cell populations that can develop resistance by multiple routes[8,9,10]. Cell death can occur via a variety of mechanisms, including apoptosis and necroptosis, and selection among
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
