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However, interpreting such data with mechanistic computational models is hindered because direct model\/data comparison is often muddled. We developed an algorithm that tracks simulated division and death events in mechanistically-detailed single-cell lineages to enable such a model\/data comparison and suggest causes of cell-cell drug response variability. Using our previously developed model of mammalian single-cell proliferation and death signaling, we simulated drug dose response experiments for four targeted anti-cancer drugs (alpelisib, neratinib, trametinib and palbociclib) and compared them to experimental data. Simulations are consistent with data for strong growth inhibition by trametinib (MEK inhibitor) and overall lack of efficacy for alpelisib (PI-3K inhibitor), but are inconsistent with data for palbociclib (CDK4\/6 inhibitor) and neratinib (EGFR inhibitor). Model\/data inconsistencies suggest that (i) the importance of CDK4\/6 for driving the cell cycle may be overestimated, and (ii) the cellular balance between basal (tonic) and ligand-induced signaling is a critical determinant of receptor inhibitor response. Simulations show subpopulations of rapidly and slowly dividing cells in both control and drug-treated conditions. Variations in mother cells prior to drug treatment impinging on ERK pathway activity are associated with the rapidly dividing phenotype and trametinib resistance. This work lays a foundation for the application of mechanistic modeling to large-scale cell viability datasets and better understanding determinants of cellular heterogeneity in drug response.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013156","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T17:59:11Z","timestamp":1756490351000},"page":"e1013156","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanistic modeling of cell viability assays with in silico lineage tracing"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6488-7067","authenticated-orcid":true,"given":"Arnab","family":"Mutsuddy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7468-4626","authenticated-orcid":true,"given":"Jonah 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