Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.

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Background: Total hip arthroplasty (THA) is the benchmark surgical treatment of advanced and symptomatic hip osteoarthritis. Preliminary evidence suggests that the robotic arm-assisted (RAA) technology yields more accurate and reproducible acetabular cup placement, which may improve survival rate and clinical results, but economic considerations are less well-defined. The purpose of this study was to compare the cost effectiveness of the RAA THA with manual THA (mTHA) modalities, considering direct medical costs and utilities from a payer's perspective. Methods: A Markov model was constructed to analyze two potential interventions for hip osteoarthritis and degenerative joint disorder: RAA THA and mTHA. Potential outcomes of THA were categorized into the transition states: infection, dislocation, no major complications, or revision. Cumulative costs and utilities were assessed using a cycle length of 1 year over a time horizon of 5 years. Results: RAA THA cohort was cost effective relative to mTHA cohort for cumulative Medicare and cumulative private payer insurance costs over the 5-year period. RAA THA cost saving had an average differential of $945 for Medicare and $1,810 for private insurance relative to mTHA while generating slightly more utility (0.04 quality-adjusted life year). The preferred treatment was sensitive to the utilities generated by successful RAA THA and mTHA. Microsimulations indicated that RAA THA was cost effective in 99.4% of cases. Conclusions: In the Medicare and private payer scenarios, RAA THA is more cost effective than conventional mTHA when considering direct medical costs from a payer's perspective. Level of Evidence: Economic Level III. Computer simulation model (Markov model)