Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds.

Autor: Blanchard CE; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Gomeiz AT; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Avery K; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Gazzah EE; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Alsubaie AM; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Sikaroodi M; Microbiome Analysis Center, George Mason University, Manassas, VA, 20110, USA., Chiari Y; Department of Biology, George Mason University, Fairfax, VA, 22030, USA.; School of Life Sciences, University of Nottingham, Nottingham, NG7 2TQ, UK., Ward C; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Sanchez J; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA., Espina V; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA., Petricoin E; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA., Baldelli E; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA., Pierobon M; School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA. mpierobo@gmu.edu.; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA. mpierobo@gmu.edu.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jul 26; Vol. 22 (1), pp. 377. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1186/s12964-024-01742-3
Abstrakt: Background: Tumor heterogeneity is a main contributor of resistance to anti-cancer targeted agents though it has proven difficult to study. Unfortunately, model systems to functionally characterize and mechanistically study dynamic responses to treatment across coexisting subpopulations of cancer cells remain a missing need in oncology.
Methods: Using single cell cloning and expansion techniques, we established monoclonal cell subpopulations (MCPs) from a commercially available epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer cell line. We then used this model sensitivity to the EGFR inhibitor osimertinib across coexisting cell populations within the same tumor. Pathway-centered signaling dynamics associated with response to treatment and morphological characteristics of the MCPs were assessed using Reverse Phase Protein Microarray. Signaling nodes differentially activated in MCPs less sensitive to treatment were then pharmacologically inhibited to identify target signaling proteins putatively implicated in promoting drug resistance.
Results: MCPs demonstrated highly heterogeneous sensitivities to osimertinib. Cell viability after treatment increased > 20% compared to the parental line in selected MCPs, whereas viability decreased by 75% in other MCPs. Reduced treatment response was detected in MCPs with higher proliferation rates, EGFR L858R expression, activation of EGFR binding partners and downstream signaling molecules, and expression of epithelial-to-mesenchymal transition markers. Levels of activation of EGFR binding partners and MCPs' proliferation rates were also associated with response to c-MET and IGFR inhibitors.
Conclusions: MCPs represent a suitable model system to characterize heterogeneous biomolecular behaviors in preclinical studies and identify and functionally test biological mechanisms associated with resistance to targeted therapeutics.
(© 2024. The Author(s).)
Databáze: MEDLINE
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